Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1 -- 3160 2023-07-06 07:17:13 |
2 layout Meta information modification 3160 2023-07-06 07:55:39 |

Video Upload Options

Do you have a full video?


Are you sure to Delete?
If you have any further questions, please contact Encyclopedia Editorial Office.
Airola, C.; Pallozzi, M.; Cerrito, L.; Santopaolo, F.; Stella, L.; Gasbarrini, A.; Ponziani, F.R. Microvascular Thrombosis and Liver Fibrosis Progression. Encyclopedia. Available online: (accessed on 24 June 2024).
Airola C, Pallozzi M, Cerrito L, Santopaolo F, Stella L, Gasbarrini A, et al. Microvascular Thrombosis and Liver Fibrosis Progression. Encyclopedia. Available at: Accessed June 24, 2024.
Airola, Carlo, Maria Pallozzi, Lucia Cerrito, Francesco Santopaolo, Leonardo Stella, Antonio Gasbarrini, Francesca Romana Ponziani. "Microvascular Thrombosis and Liver Fibrosis Progression" Encyclopedia, (accessed June 24, 2024).
Airola, C., Pallozzi, M., Cerrito, L., Santopaolo, F., Stella, L., Gasbarrini, A., & Ponziani, F.R. (2023, July 06). Microvascular Thrombosis and Liver Fibrosis Progression. In Encyclopedia.
Airola, Carlo, et al. "Microvascular Thrombosis and Liver Fibrosis Progression." Encyclopedia. Web. 06 July, 2023.
Microvascular Thrombosis and Liver Fibrosis Progression

Fibrosis is a frequent consequence of organ injury. The formation of an extracellular matrix (ECM) depends on a complex cascade of cellular and molecular pathways, the chronic activation of which results in a sustained fibrogenic process that leads to structural changes and, ultimately, to dysfunction of the affected organ. Thus, fibrosis is a major contributor to organ failure in human pathophysiology.

ADAMTS-13 coagulation fibrosis hepatic stellate cells liver cirrhosis

1. Introduction

Fibrosis is a frequent consequence of organ injury. The formation of an extracellular matrix (ECM) depends on a complex cascade of cellular and molecular pathways, the chronic activation of which results in a sustained fibrogenic process that leads to structural changes and, ultimately, to dysfunction of the affected organ. Thus, fibrosis is a major contributor to organ failure in human pathophysiology [1]. Fibrotic changes are linked to a variety of diseases, suggesting common pathogenetic mechanisms. This “wound response” is controlled by complex cell-specific processes in which distinct molecular pathways are involved [1]. Hemostasis is becoming increasingly important among the many biochemical mechanisms and cellular interactions involved in fibrogenesis.
The development of chronic disease following organ damage has been linked to an imbalance between pro- and anti-coagulant factors. For example, microvascular endothelial cells of the renal parenchyma contribute to the development of a prothrombotic environment in the presence of stressor triggers by increasing the synthesis of prohemostatic factors and reducing the production of protective proteins. Activation of the endothelial surface following the onset of thrombosis and activation of the coagulation cascade induces transformation to a proinflammatory fibrogenic cellular phenotype, which worsens renal damage and causes fibrosis [2]. Additionally, in acute lung injury and fibrotic lung disease, uncontrolled coagulation has been shown to contribute to the dysregulation of inflammatory and fibroproliferative responses [3]. According to pathophysiological evidence, coagulation plays an essential role in many disorders, and fibrosis is often an adverse outcome. Chronic liver disease is the paradigm of conditions in which fibrosis resulting from an acute or chronic insult leads to organ dysfunction.

2. From Microvascular Thrombosis to Hepatic Fibrosis

Studies on the consequences of acute murine hepatitis virus infection have provided the first evidence that coagulation is an important factor in the pathogenesis of liver disease. Indeed, numerous sinusoidal microthrombi directly related to hepatic parenchymal necrosis were described in these animal models, and microvascular thrombosis was associated with more severe hepatitis [4][5][6].
In 1995, examining histological specimens from the livers of patients with chronic heart failure, Wanless et al. found a substantial correlation between sinusoidal fibrosis and the occurrence of local thrombotic events, indicating that liver fibrosis may be the result of microvascular thrombosis. More specifically, it has been proposed that disruption of blood flow by sinusoidal microthrombi and sinusoidal fibrosis cause reactive hyperemia and congestion, which activate fibroblasts and increase collagen deposition, worsening blood flow, inducing extension of thrombosis, neoangiogenesis, and parenchymal necrosis. The end result is the loss of hepatocytes and the formation of fibrous septa that completely alter the architecture of the liver [7]. The replacement of liver parenchyma with fibrotic tissue as a result of microvascular disruption has been called parenchymal extinction [8]. Inflammation is considered to be one of the main mechanisms inducing hepatic fibrogenesis in response to parenchymal damage [9]; however, a preclinical model has shown that mild inflammation at both histological and serological levels is associated with the development of liver fibrosis due to chronic venous congestion [10]. According to this study, sinusoidal thrombosis appears to be crucially involved in the direct potentiation of fibrogenesis in congestive liver disease.
On the other hand, hemostasis has also been firmly linked to the inflammatory response, and recently the concepts of immune-coagulation and thrombo-inflammation have been proposed [11][12]. Several conditions, including ischemia-reperfusion syndrome and infections, can lead to the formation of microvascular thrombosis, which triggers an inflammatory response [13]. As part of inflammatory processes, numerous cell types, including immune cells and fibroblasts, participate in the coagulation process, enhancing inflammation and increasing ECM deposition in different organs [14]. In fact, hemostatic activation could be both the cause and the consequence of the inflammatory process.
However, there are few examples of clinical models of hepatic microvascular thrombosis in the literature, probably because microvascular thrombosis is rapidly replaced by fibrous tissue and is rarely detected on biopsy in patients with chronic liver disorders [8]. Cases of systemic microvascular thrombotic disease in humans suddenly increased following the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, prompting multiple studies, including some on liver pathology. SARS-CoV-2 causes COVID-19, which is a systemic infectious disease in which endothelial cell dysfunction and microvascular thrombosis are likely to play a major role in the development of multi-organ complications [15]. Although the airways and lungs are the main organs affected by SARS-CoV-2, liver injury is a frequent condition in patients with the most severe clinical forms [16][17]. Sinusoidal microthrombi were frequent in liver biopsy specimens taken from COVID-19 patients and were related to more severe liver damage [18][19]. Mild portal and lobular inflammation, confluent parenchymal necrosis, and fibrosis are other histological findings [18]. Because there is no evidence of direct cytopathic virus damage, the latter appears to be associated with the marked inflammatory activation produced by the infection [20]; in fact, molecular analyses revealed that during severe COVID-19, genes frequently linked to hepatic stellate cells (HSCs) activation and liver fibrosis, such as interleukin 6 (IL6), interleukin 1 (IL1), tumor necrosis factor α (TNF-α), interleukin 10 (IL10), and interferon α (IFN-α), as well as vascular endothelial growth factor (VEGF) and monocyte chemoattractant protein 1 (MCP-1), are overexpressed [21]. In addition, a higher noninvasive fibrosis score appears to be correlated with a higher risk of developing severe COVID-19 [22].
The fascinating link between sinusoidal thrombosis and the activation of molecular pathways of liver fibrosis in humans is supported by the beneficial effects of anticoagulants on the development of fibrosis [23][24]. In line with the direction set out by Wanless et al. in 1995, developments in molecular medicine and the identification of new intra- and intercellular networks have strengthened this connection.

3. Hepatic Stellate Cells and Protease Activated Receptor

In response to repeated injury, HSCs can differentiate into myofibroblasts, which proliferate and produce ECM [25]. In addition, HSCs stimulate other cell types that participate in the inflammatory response and fibrogenesis through the production of growth factors and chemokines, playing a critical role in driving the initiation and progression of the fibrogenic process [26]. As expected, microvascular sinusoidal thrombosis, which leads to ischemic injury and inflammatory response, causes overexpression of VEGF, platelet-derived growth factor (PDGF) and transforming growth factor beta (TGFβ) by hepatocytes and HSCs, as well as increased synthesis of type I and type IV collagen by activated HSCs [27]. However, a specific molecular mechanism has been proposed as responsible for the apparent association between microvascular thrombosis and fibrogenesis. In 1998, Marra et al. hypothesized that the protease-activated receptor (PAR) signaling pathway was a major molecular pathway involved in HSCs activation and hepatic scarring [28]. PARs are G-protein-coupled receptors with proteolytic activity that stimulate cellular responses by interacting with coagulation factor Xa (FXa) and neutrophil elastase (PAR 1, 2), thrombin (PAR 1, 3, 4), coagulation factor VIIa (PAR 1), and tryptase (PAR 2, 4), which cleave the N-terminal of the receptor [28]. PARs are expressed by different types of cells involved in the fine regulation of vascular homeostasis, and their signaling pathways are complex because they can be linked to G proteins with different functions. Consequently, they interact with a myriad of signaling transducers (e.g., extracellular signal-regulated kinase [ERK] 1/2, Rho/Rho-kinase, c-Jun N-terminal kinase, inositol 1,4,5-trisphosphate [IP3], phosphoinositide 3-kinases [PI3K], and Janus kinase/signal transducers and activators of transcription [JAK-STAT]), resulting in pleiotropic effects [29][30][31]. PARs have been linked to the progression of fibrosis in several organs, and because they have a high affinity for factors in the coagulation cascade, they have been proposed as the main link between hemostasis and pulmonary fibrosis [32][33] or renal fibrosis [2]. In addition, PAR 1 induces cardiac fibroblast activation in response to thrombin or FXa and, by modulating the ERK1/2 pathway, leads to cardiac remodeling and fibrosis [29][34].
PARs are found in liver cells and are abundantly overexpressed in chronic liver disease, as in the case of PAR 1 in the myofibroblast group of cirrhotic individuals [35]. A preclinical rat liver stellate cell model revealed a progressive increase in PAR 1 and PAR 2 expression during transformation to a myofibroblastic phenotype [36]. Increasing concentrations of thrombin transform HSCs into myofibroblasts increases the production of α-smooth muscle actin (α-SMA), pro-collagen, TGFβ-1, matrix metalloproteinase 2 (MMP-2), and other cellular signals essential for wound healing [37][38]. Furthermore, when HSCs are treated with a combination of FXa and thrombin, there is an increase in α-SMA, procollagen, TGFβ-1, and significantly improved cell contraction compared with FXa or thrombin alone [39].
Preclinical studies have confirmed the importance of PARs in fibrogenesis, showing how inhibition or lack of PAR 1 and PAR 2 reduces the evolution of liver fibrosis [38][40].
However, this evidence about coagulation factor-mediated HSCs activation by PAR has been based mainly on in vitro research. Poole et al. recently studied the effect on the liver of chronic exposure to carbon tetrachloride (CCl4) in vivo, using a mouse model with PAR 1 deletion specific for HSCs. PAR 1 deletion was linked to decreased activation of HSCs and collagen deposition but was not protective against acute liver damage after CCl4 exposure [41]. Thus, PAR 1 appears to play a role in the “healing process” that occurs after liver injury rather than in its acute phase. Indeed, enoxaparin treatment significantly reduced portal hypertension, hepatic fibrosis, HSCs activation, and desmin expression in mice with CCl4-induced cirrhosis without having any effect on the acute injury. In addition, molecular analysis revealed decreased hepatic fibrin deposition in enoxaparin-treated rats, implying the role of intrahepatic microthrombosis as a primary mechanism of PAR activation [23].
Regarding the etiology of liver fibrosis, thrombin-mediated HSC activation appears to be closely related to the progression of nonalcoholic fatty liver disease (NAFLD) [42]. In addition, administration of a direct thrombin inhibitor to mice with NAFLD reduces HSCs activation, α-SMA expression, and hepatic collagen type 1 mRNA levels [42]. While thrombin has been shown to play a crucial role in the progression of NAFLD, a preclinical investigation suggested that PAR 1, its receptor, is essential for the development of hepatic steatosis in mice fed a Western diet [43]. Nault et al. studied the involvement of PAR 1 signaling in liver damage caused by the contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). C57BL/6 mice exposed to TCDD acquire NAFLD-like features, such as steatosis, liver damage, inflammation, and fibrosis. Subchronic exposure to TCDD also causes increased intrahepatic coagulation, as reflected by increased thrombin production and deposition of fibrin and fibrinogen in the liver. As measured by serum alanine aminotransferase activity, PAR 1 deficiency had no effect on TCDD-induced hepatocellular damage and hepatic lipid accumulation but nevertheless was linked to a significant reduction in liver fibrosis and histologic evidence of inflammation [44].
Although the function of microvascular thrombosis in the evolution of a chronic disease such as NAFLD seems well established, in contrast, the importance of PARs in the progression of chronic viral hepatitis to fibrosis has been less studied. One study examined the PAR 1 genotype in people with chronic HCV infection and found that a specific PAR 1 polymorphism (1426 C/T) was linked to histological evidence of increased liver fibrosis [45]. However, the role of PAR 1 in the progression of viral hepatitis-related liver fibrosis is mainly unknown. The PAR signaling pathway of HSCs is currently believed to be the main element explaining the direct association between microvascular thrombosis and fibrogenesis in the liver parenchyma, although there may be variations depending on the etiology of liver disease. It is also possible to hypothesize a different role of PAR 1 expressed by different cell types; in fact, a number of non-parenchymal liver cells and other cells that infiltrate the damaged liver, including sinusoidal endothelial cells, inflammatory cells (monocytes, neutrophils, and lymphocytes), resident hepatic macrophages (Kupffer cells), and bile duct epithelial cells may express PAR 1 [46][47][48]. Therefore, since microvascular thrombosis may be a manifestation of a harmful hepatic stimulation, PAR 1 activation of HSCs may be the primary cause of the abnormal response leading to fibrosis and its progression. However, considering the wide variety of interactions that occur during hepatic fibrogenesis, it may not be the only one and may indeed be part of a more complex network of molecular and cellular pathways yet to be defined.

4. The Role of Liver Sinusoidal Endothelial Cells and Neutrophil Extracellular Traps

Another important cell type involved in the relationship between microvascular thrombosis and fibrosis progression is hepatic sinusoidal endothelial cells (LSECs). It is commonly recognized that LSECs interact with other cells, such as neutrophils, lymphocytes, HSCs, hepatocytes, and Kupffer cells, which is critical in the progression of nonalcoholic steatohepatitis (NASH) to fibrosis [49]. Healthy endothelial cells, on the other hand, express molecules that inhibit platelet activation, coagulation, and thrombosis [50]. Expression of pro- and anti-thrombotic elements changes when LSECs lose their antithrombotic phenotype due to endothelial dysfunction [51][52]. The expression of thrombomodulin, nitric oxide, or prostaglandin I2 is attenuated in the presence of dysfunctional LSECs, which also expose Von Willebrand factor (VWF), integrins, and other receptors that interact with activated platelets and cause clot formation [53][54]. It has also been shown that hepatitis viruses, including hepatitis B virus (HBV) and murine acute hepatitis virus 3, a member of the Coronaviridae, can induce LSECs to overexpress Fgl2/fibroleukin prothrombinase, which is crucial for the initiation and progression of fibrin deposition [55][56][57]. Recent histological and molecular studies in a mouse model of congestive hepatopathy demonstrated that LSECs exposed to mechanical stretch upregulate Notch-dependent transcription factors through an integrin-dependent pathway and interaction with the mechanosensitive piezo-calcium channel. As a result, LSECs increase the production of neutrophil chemoattractant C-X-C motif ligand (CXCL) 1, attracting platelets and neutrophils into hepatic sinusoids and leading to the formation of extracellular neutrophil traps (NETs). NETs are complexes consisting of a backbone of extracellular DNA fibers bound to histones and granular proteins, such as myeloperoxidase and neutrophil elastase, which are strongly linked to sinusoidal thrombosis [58]. Interestingly, the progression of NASH has been linked to parenchymal neutrophil infiltration and NET development in mice [59]. In addition, in biopsy samples of the lungs, liver, and kidneys from patients with severe COVID-19, NETs have been linked to microvascular thrombosis [60][61]. As previously shown, when LSECs are dysfunctional, they lose their antithrombotic activity, promoting local thrombotic events and, consequently, the progression of PAR 1-induced fibrosis. In addition, LSECs themselves overexpress PAR 1, which is activated by the coagulation cascade in response to injury, as was demonstrated in a preclinical model of ischemia in mouse liver. In LSECs, PAR 1 activation blocks the ERK1/2 pathway and promotes apoptotic signaling, exacerbating liver damage and causing inflammation and fibrosis [62]. Kruppel-like factor 2 (KFL2), a transcription factor, has recently been recognized as a crucial regulator of endothelium homeostasis in response to inflammatory stimuli, coagulation factors, and hemodynamic stresses such as laminar shear stress [63][64][65]. In LSECs of cirrhotic mice, transcriptome analysis revealed downregulation of Kruppel-like factor (KLF) 2 and 4. In addition, Marrone et al. showed that overexpression of KLF2 in LSECs and HSCs derived from cirrhotic rats reduces HSC activation and enhances paracrine cross-talk between LSECs [66][67]. This is consistent with the decrease in fibrosis and portal pressure associated with KFL2 overexpression in animal studies [68]. Interestingly, KLF2 is primarily activated by the extracellular signal-regulated kinase 5 (MEK5)-extracellular signal-regulated kinase 5 (ERK5) pathway [69], the overexpression of which has recently been linked to suppression of PAR 1 signaling in cell types such as pneumocytes and alveolar barrier endothelial cells [70]. Further research revealed the function of the long noncoding RNA Airn in controlling KLF2. In fact, Airn interacts with subunit 2 of the Polycomb Enhancer Of Zeste 2 repressive complex to maintain the differentiation of LSECs through the KLF2 pathway, preventing the capillarization of LSECs, maintaining the quiescence of HSCs and attenuating the progression of fibrosis. Airn is highly expressed in the liver and serum of patients with fibrosis and in mouse fibrotic livers [71].

5. ADAMTS 13—Von Willebrand Factor, a Bridge between Coagulation and Fibrosis

Liver cirrhosis has long been considered an acquired bleeding condition because of altered coagulation parameters. Indeed, there is a reduction in liver-related coagulation factors, such as Factors II, V, VII, IX, and XI, but levels of vitamin K-dependent anticoagulant proteins, protein C (PC), protein S, and antithrombin III are also reduced [72][73]. However, it is now recognized that the risk of bleeding is not a consequence of coagulation imbalance but is related to portal hypertension, and that cirrhotic patients maintain a perfect hemostatic balance in most cases [74]. In fact, studies by Tripodi et al. proved that the thrombin generation assay remains preserved in these patients despite these alterations [75][76]. Increased levels of Factor VIII (FVIII) and VWF have also been observed in cirrhotic patients with portal hypertension, suggesting that a procoagulant milieu may prevail [77][78].
These factors are produced and stored in the endothelial cells of portal and hepatic veins but not in hepatic sinusoids [79]. However, in advanced stages of liver fibrosis, endothelial cells of hepatic sinusoids acquire the phenotype of vascular endothelium due to chronic inflammation and endotoxemia, which are the main contributors to portal hypertension [80][81][82][83][84], and begin to produce FVIII and VWF. VWF is a multimeric glycoprotein synthetized and released by vascular endothelial cells in the bloodstream in the form of multimers, with the ability to bind platelets proportionally to their size, demonstrating a pivotal role in hemostatic balance [85]. It is stored in Weibel–Palade bodies (WPBs) and excreted upon stimulation. Some studies have shown a direct correlation between circulating FVIII levels and the severity of portal hypertension as measured by hepatic venous pressure gradient (HVPG) or the presence of ascites and the risk of variceal hemorrhage in patients with advanced liver disease [80][81][82][83][84]. In addition, the association between FVIII alterations and liver fibrosis is well-known: in particular, FVIII and VWF have been observed in capillaries and pericellular regions alongside necrotic sites in the liver parenchyma, and inflammatory injury may promote the deposition of these factors along with fibrosis [86]. A Disintegrin and Metalloproteinase with a Thrombospondin Type 1 motif, member 13 (ADAMTS-13), is another factor influenced by chronic inflammation and advanced liver disease. It is a metalloproteinase that cuts the multimeric VWF between Tyr1605 and Met1606 in its A2 domain. ADAMTS-13 is mainly produced in the liver by HSCs [87][88][89][90][91], and finely regulates hemostatic balance by controlling the size of VWF multimeters, thus their ability to aggregate platelets by forming microthrombi. In chronic liver disease, HSCs that acquire a myofibroblastic phenotype lose the ability to produce and store ADAMTS-13 [89][92][93][94].
Moreover, ADAMTS-13 is inversely correlated with the severity of liver dysfunction in terms of antigen production and activity, whereas VWF antigen and activity increase, as previously discussed, resulting in the release of high molecular weight VWF (HMWVWF) multimers [95].
Therefore, ADAMTS-13 and VWF imbalance may have a pivotal role in the paradigm of parenchymal extinction and liver fibrosis progression in chronic liver diseases [96][97]; indeed, the upregulation of VWF levels in the presence of chronic inflammation, vascular damage, or endotoxemia [80][81] is not counterbalanced due to the deficiency of ADAMTS-13, promoting the formation of platelet microthrombi and fibrin deposition in hepatic sinusoids, with the loss of liver parenchyma and fibrogenesis [98][99].
This condition is similar to thrombotic thrombocytopenic purpura, a primary or acquired clinical disorder induced by the loss of ADAMTS-13 activity or its deficiency that lead to microthrombi formation in small vessels such as glomeruli, cerebral vessels, and cutaneous capillaries [93][99][100][101].


  1. Rockey, D.C.; Bell, P.D.; Hill, J.A. Fibrosis—A Common Pathway to Organ Injury and Failure. N. Engl. J. Med. 2015, 372, 1138–1149.
  2. Jourde-Chiche, N.; Fakhouri, F.; Dou, L.; Bellien, J.; Burtey, S.; Frimat, M.; Jarrot, P.-A.; Kaplanski, G.; Le Quintrec, M.; Pernin, V.; et al. Endothelium Structure and Function in Kidney Health and Disease. Nat. Rev. Nephrol. 2019, 15, 87–108.
  3. Chambers, R.C.; Scotton, C.J. Coagulation Cascade Proteinases in Lung Injury and Fibrosis. Proc. Am. Thorac. Soc. 2012, 9, 96–101.
  4. Macphee, P.J.; Dindzans, V.J.; Fung, L.-S.; Levy, G.A. Acute and Chronic Changes in the Microcirculation of the Liver in Inbred Strains of Mice Following Infection with Mouse Hepatitis Virus Type 3. Hepatology 1985, 5, 649–660.
  5. MacPhee, P.J.; Schmidt, E.E.; Keown, P.A.; Groom, A.C. Microcirculatory Changes in Livers of Mice Infected with Murine Hepatitis Virus. Evidence from Microcorrosion Casts and Measurements of Red Cell Velocity. Microvasc. Res. 1988, 36, 140–149.
  6. Levy, G.A.; Macphee, P.J.; Fung, L.S.; Fisher, M.M.; Rappaport, A.M. The Effect of Mouse Hepatitis Virus Infection on the Microcirculation of the Liver. Hepatology 2007, 3, 964–973.
  7. Wanless, I.R.; Liu, J.J.; Butany, J. Role of Thrombosis in the Pathogenesis of Congestive Hepatic Fibrosis (Cardiac Cirrhosis). Hepatology 1995, 21, 1232–1237.
  8. Wanless, I.R. The Role of Vascular Injury and Congestion in the Pathogenesis of Cirrhosis: The Congestive Escalator and the Parenchymal Extinction Sequence. Curr. Hepatol. Rep. 2020, 19, 40–53.
  9. Bissell, D. Inflammation and Hepatic Fibrosis. Semin. Liver Dis. 2010, 30, 211–214.
  10. Simonetto, D.A.; Yang, H.; Yin, M.; de Assuncao, T.M.; Kwon, J.H.; Hilscher, M.; Pan, S.; Yang, L.; Bi, Y.; Beyder, A.; et al. Chronic Passive Venous Congestion Drives Hepatic Fibrogenesis via Sinusoidal Thrombosis and Mechanical Forces. Hepatology 2015, 61, 648–659.
  11. Martinod, K.; Deppermann, C. Immunothrombosis and Thromboinflammation in Host Defense and Disease. Platelets 2021, 32, 314–324.
  12. Tang, D.; Wang, H.; Billiar, T.R.; Kroemer, G.; Kang, R. Emerging Mechanisms of Immunocoagulation in Sepsis and Septic Shock. Trends Immunol. 2021, 42, 508–522.
  13. Sharma, S.; Tyagi, T.; Antoniak, S. Platelet in Thrombo-Inflammation: Unraveling New Therapeutic Targets. Front. Immunol. 2022, 13, 1039843.
  14. Oh, H.; Park, H.E.; Song, M.S.; Kim, H.; Baek, J.-H. The Therapeutic Potential of Anticoagulation in Organ Fibrosis. Front. Med. 2022, 9, 866746.
  15. Nalugo, M.; Schulte, L.J.; Masood, M.F.; Zayed, M.A. Microvascular Angiopathic Consequences of COVID-19. Front. Cardiovasc. Med. 2021, 8, 636843.
  16. Leo, M.; Galante, A.; Pagnamenta, A.; Ruinelli, L.; Ponziani, F.R.; Gasbarrini, A.; De Gottardi, A. Hepatocellular Liver Injury in Hospitalized Patients Affected by COVID-19: Presence of Different Risk Factors at Different Time Points. Dig. Liver Dis. 2022, 54, 565–571.
  17. Ponziani, F.R.; Del Zompo, F.; Nesci, A.; Santopaolo, F.; Ianiro, G.; Pompili, M.; Gasbarrini, A. “Gemelli against COVID-19” group. Liver Involvement Is Not Associated with Mortality: Results from a Large Cohort of SARS-CoV-2 Positive Patients. Aliment. Pharmacol. Ther. 2020, 52, 1060–1068.
  18. Sonzogni, A.; Previtali, G.; Seghezzi, M.; Grazia Alessio, M.; Gianatti, A.; Licini, L.; Morotti, D.; Zerbi, P.; Carsana, L.; Rossi, R.; et al. Liver Histopathology in Severe COVID 19 Respiratory Failure Is Suggestive of Vascular Alterations. Liver Int. 2020, 40, 2110–2116.
  19. Kondo, R.; Kawaguchi, N.; McConnell, M.J.; Sonzogni, A.; Licini, L.; Valle, C.; Bonaffini, P.A.; Sironi, S.; Alessio, M.G.; Previtali, G.; et al. Pathological Characteristics of Liver Sinusoidal Thrombosis in COVID-19 Patients: A Series of 43 Cases. Hepatol. Res. 2021, 51, 1000–1006.
  20. Del Zompo, F.; De Siena, M.; Ianiro, G.; Gasbarrini, A.; Pompili, M.; Ponziani, F.R. Prevalence of Liver Injury and Correlation with Clinical Outcomes in Patients with COVID-19: Systematic Review with Meta-Analysis. Eur. Rev. Med. Pharmacol. Sci. 2020, 24, 13072–13088.
  21. Moya, L.; Farashi, S.; Suravajhala, P.; Janaththani, P.; Batra, J. Severe COVID-19 May Impact Hepatic Fibrosis /Hepatic Stellate Cells Activation as Indicated by a Pathway and Population Genetic Study. Genes 2022, 14, 22.
  22. Targher, G.; Mantovani, A.; Byrne, C.D.; Wang, X.-B.; Yan, H.-D.; Sun, Q.-F.; Pan, K.-H.; Zheng, K.I.; Chen, Y.-P.; Eslam, M.; et al. Risk of Severe Illness from COVID-19 in Patients with Metabolic Dysfunction-Associated Fatty Liver Disease and Increased Fibrosis Scores. Gut 2020, 69, 1545–1547.
  23. Cerini, F.; Vilaseca, M.; Lafoz, E.; García-Irigoyen, O.; García-Calderó, H.; Tripathi, D.M.; Avila, M.; Reverter, J.C.; Bosch, J.; Gracia-Sancho, J.; et al. Enoxaparin Reduces Hepatic Vascular Resistance and Portal Pressure in Cirrhotic Rats. J. Hepatol. 2016, 64, 834–842.
  24. Vilaseca, M.; García-Calderó, H.; Lafoz, E.; García-Irigoyen, O.; Avila, M.A.; Reverter, J.C.; Bosch, J.; Hernández-Gea, V.; Gracia-Sancho, J.; García-Pagán, J.C. The Anticoagulant Rivaroxaban Lowers Portal Hypertension in Cirrhotic Rats Mainly by Deactivating Hepatic Stellate Cells. Hepatology 2017, 65, 2031–2044.
  25. Liedtke, C.; Nevzorova, Y.A.; Luedde, T.; Zimmermann, H.; Kroy, D.; Strnad, P.; Berres, M.-L.; Bernhagen, J.; Tacke, F.; Nattermann, J.; et al. Liver Fibrosis—From Mechanisms of Injury to Modulation of Disease. Front. Med. 2022, 8, 814496.
  26. Lee, U.E.; Friedman, S.L. Mechanisms of Hepatic Fibrogenesis. Best Pract. Res. Clin. Gastroenterol. 2011, 25, 195–206.
  27. Corpechot, C.; Barbu, V.; Wendum, D.; Kinnman, N.; Rey, C.; Poupon, R.; Housset, C.; Rosmorduc, O. Hypoxia-Induced VEGF and Collagen I Expressions Are Associated with Angiogenesis and Fibrogenesis in Experimental Cirrhosis: Hypoxia-Induced VEGF and Collagen I Expressions Are Associated with Angiogenesis and Fibrogenesis in Experimental Cirrhosis. Hepatology 2002, 35, 1010–1021.
  28. Riewald, M. Orchestration of Coagulation Protease Signaling by Tissue Factor. Trends Cardiovasc. Med. 2002, 12, 149–154.
  29. Peach, C.J.; Edgington-Mitchell, L.E.; Bunnett, N.W.; Schmidt, B.L. Protease-Activated Receptors in Health and Disease. Physiol. Rev. 2023, 103, 717–785.
  30. Kataoka, H.; Hamilton, J.R.; McKemy, D.D.; Camerer, E.; Zheng, Y.-W.; Cheng, A.; Griffin, C.; Coughlin, S.R. Protease-Activated Receptors 1 and 4 Mediate Thrombin Signaling in Endothelial Cells. Blood 2003, 102, 3224–3231.
  31. Martorell, L.; Martínez-González, J.; Rodríguez, C.; Gentile, M.; Calvayrac, O.; Badimon, L. Thrombin and Protease-Activated Receptors (PARs) in Atherothrombosis. Thromb. Haemost. 2008, 99, 305–315.
  32. Lin, C.; von der Thüsen, J.; Daalhuisen, J.; ten Brink, M.; Crestani, B.; van der Poll, T.; Borensztajn, K.; Spek, C.A. Protease-Activated Receptor (PAR)-2 Is Required for PAR-1 Signalling in Pulmonary Fibrosis. J. Cell Mol. Med. 2015, 19, 1346–1356.
  33. Wygrecka, M.; Kwapiszewska, G.; Jablonska, E.; von Gerlach, S.; Henneke, I.; Zakrzewicz, D.; Guenther, A.; Preissner, K.T.; Markart, P. Role of Protease-Activated Receptor-2 in Idiopathic Pulmonary Fibrosis. Am. J. Respir. Crit. Care Med. 2011, 183, 1703–1714.
  34. Yokono, Y.; Hanada, K.; Narita, M.; Tatara, Y.; Kawamura, Y.; Miura, N.; Kitayama, K.; Nakata, M.; Nozaka, M.; Kato, T.; et al. Blockade of PAR-1 Signaling Attenuates Cardiac Hypertrophy and Fibrosis in Renin-Overexpressing Hypertensive Mice. J. Am. Heart Assoc. 2020, 9, e015616.
  35. Ramachandran, P.; Dobie, R.; Wilson-Kanamori, J.R.; Dora, E.F.; Henderson, B.E.P.; Luu, N.T.; Portman, J.R.; Matchett, K.P.; Brice, M.; Marwick, J.A.; et al. Resolving the Fibrotic Niche of Human Liver Cirrhosis at Single-Cell Level. Nature 2019, 575, 512–518.
  36. Gaça, M.D.A.; Zhou, X.; Benyon, R.C. Regulation of Hepatic Stellate Cell Proliferation and Collagen Synthesis by Proteinase-Activated Receptors. J. Hepatol. 2002, 36, 362–369.
  37. Chambers, R.C.; Dabbagh, K.; McANULTY, R.J.; Gray, A.J.; Blanc-Brude, O.P.; Laurent, G.J. Thrombin Stimulates Fibroblast Procollagen Production via Proteolytic Activation of Protease-Activated Receptor 1. Biochem. J. 1998, 333, 121–127.
  38. Rullier, A.; Gillibert-Duplantier, J.; Costet, P.; Cubel, G.; Haurie, V.; Petibois, C.; Taras, D.; Dugot-Senant, N.; Deleris, G.; Bioulac-Sage, P.; et al. Protease-Activated Receptor 1 Knockout Reduces Experimentally Induced Liver Fibrosis. Am. J. Physiol.-Gastrointest. Liver Physiol. 2008, 294, G226–G235.
  39. Dhar, A.; Sadiq, F.; Anstee, Q.M.; Levene, A.P.; Goldin, R.D.; Thursz, M.R. Thrombin and Factor Xa Link the Coagulation System with Liver Fibrosis. BMC Gastroenterol. 2018, 18, 60.
  40. Fiorucci, S.; Antonelli, E.; Distrutti, E.; Severino, B.; Fiorentina, R.; Baldoni, M.; Caliendo, G.; Santagada, V.; Morelli, A.; Cirino, G. PAR1 Antagonism Protects against Experimental Liver Fibrosis. Role of Proteinase Receptors in Stellate Cell Activation. Hepatology 2004, 39, 365–375.
  41. Poole, L.G.; Pant, A.; Cline-Fedewa, H.M.; Williams, K.J.; Copple, B.L.; Palumbo, J.S.; Luyendyk, J.P. Liver Fibrosis Is Driven by Protease-activated Receptor-1 Expressed by Hepatic Stellate Cells in Experimental Chronic Liver Injury. Res. Pract. Thromb. Haemost. 2020, 4, 906–917.
  42. Kassel, K.M.; Sullivan, B.P.; Cui, W.; Copple, B.L.; Luyendyk, J.P. Therapeutic Administration of the Direct Thrombin Inhibitor Argatroban Reduces Hepatic Inflammation in Mice with Established Fatty Liver Disease. Am. J. Pathol. 2012, 181, 1287–1295.
  43. Kassel, K.M.; Owens, A.P.; Rockwell, C.E.; Sullivan, B.P.; Wang, R.; Tawfik, O.; Li, G.; Guo, G.L.; Mackman, N.; Luyendyk, J.P. Protease-Activated Receptor 1 and Hematopoietic Cell Tissue Factor Are Required for Hepatic Steatosis in Mice Fed a Western Diet. Am. J. Pathol. 2011, 179, 2278–2289.
  44. Nault, R.; Fader, K.A.; Kopec, A.K.; Harkema, J.R.; Zacharewski, T.R.; Luyendyk, J.P. From the Cover: Coagulation-Driven Hepatic Fibrosis Requires Protease Activated Receptor-1 (PAR-1) in a Mouse Model of TCDD-Elicited Steatohepatitis. Toxicol. Sci. 2016, 154, 381–391.
  45. Martinelli, A.; Knapp, S.; Anstee, Q.; Worku, M.; Tommasi, A.; Zucoloto, S.; Goldin, R.; Thursz, M. Effect of a Thrombin Receptor (Protease-Activated Receptor 1, PAR-1) Gene Polymorphism in Chronic Hepatitis C Liver Fibrosis. J. Gastroenterol. Hepatol. 2008, 23, 1403–1409.
  46. Rullier, A.; Senant, N.; Kisiel, W.; Bioulac-Sage, P.; Balabaud, C.; Le Bail, B.; Rosenbaum, J. Expression of Protease-Activated Receptors and Tissue Factor in Human Liver. Virchows Arch. 2006, 448, 46–51.
  47. Sullivan, B.P.; Weinreb, P.H.; Violette, S.M.; Luyendyk, J.P. The Coagulation System Contributes to AVβ6 Integrin Expression and Liver Fibrosis Induced by Cholestasis. Am. J. Pathol. 2010, 177, 2837–2849.
  48. Copple, B.L.; Moulin, F.; Hanumegowda, U.M.; Ganey, P.E.; Roth, R.A. Thrombin and Protease-Activated Receptor-1 Agonists Promote Lipopolysaccharide-Induced Hepatocellular Injury in Perfused Livers. J. Pharmacol. Exp. Ther. 2003, 305, 417–425.
  49. Du, W.; Wang, L. The Crosstalk Between Liver Sinusoidal Endothelial Cells and Hepatic Microenvironment in NASH Related Liver Fibrosis. Front. Immunol. 2022, 13, 936196.
  50. Poisson, J.; Lemoinne, S.; Boulanger, C.; Durand, F.; Moreau, R.; Valla, D.; Rautou, P.-E. Liver Sinusoidal Endothelial Cells: Physiology and Role in Liver Diseases. J. Hepatol. 2017, 66, 212–227.
  51. Peralta, C.; Jiménez-Castro, M.B.; Gracia-Sancho, J. Hepatic Ischemia and Reperfusion Injury: Effects on the Liver Sinusoidal Milieu. J. Hepatol. 2013, 59, 1094–1106.
  52. Maslak, E.; Gregorius, A.; Chlopicki, S. Liver Sinusoidal Endothelial Cells (LSECs) Function and NAFLD; NO-Based Therapy Targeted to the Liver. Pharmacol. Rep. 2015, 67, 689–694.
  53. Limmer, A.; Ohl, J.; Kurts, C.; Ljunggren, H.-G.; Reiss, Y.; Groettrup, M.; Momburg, F.; Arnold, B.; Knolle, P.A. Efficient Presentation of Exogenous Antigen by Liver Endothelial Cells to CD8+ T Cells Results in Antigen-Specific T-Cell Tolerance. Nat. Med. 2000, 6, 1348–1354.
  54. Shetty, S.; Weston, C.J.; Oo, Y.H.; Westerlund, N.; Stamataki, Z.; Youster, J.; Hubscher, S.G.; Salmi, M.; Jalkanen, S.; Lalor, P.F.; et al. Common Lymphatic Endothelial and Vascular Endothelial Receptor-1 Mediates the Transmigration of Regulatory T Cells across Human Hepatic Sinusoidal Endothelium. J. Immunol. 2011, 186, 4147–4155.
  55. Zhu, C.-L. Fibrinogen-like Protein 2 Fibroleukin Expression and Its Correlation with Disease Progression in Murine Hepatitis Virus Type 3-Induced Fulminant Hepatitis and in Patients with Severe Viral Hepatitis B. World J. Gastroenterol. 2005, 11, 6936.
  56. Zhu, C.; Sun, Y.; Luo, X.; Yan, W.; Xi, D.; Ning, Q. Novel Mfgl2 Antisense Plasmid Inhibits Murine Fgl2 Expression and Ameliorates Murine Hepatitis Virus Type 3-Induced Fulminant Hepatitis in BALB/CJ Mice. Hum. Gene Ther. 2006, 17, 589–600.
  57. Marsden, P.A.; Ning, Q.; Fung, L.S.; Luo, X.; Chen, Y.; Mendicino, M.; Ghanekar, A.; Scott, J.A.; Miller, T.; Chan, C.W.Y.; et al. The Fgl2/Fibroleukin Prothrombinase Contributes to Immunologically Mediated Thrombosis in Experimental and Human Viral Hepatitis. J. Clin. Investig. 2003, 112, 58–66.
  58. Hilscher, M.B.; Sehrawat, T.; Arab, J.P.; Zeng, Z.; Gao, J.; Liu, M.; Kostallari, E.; Gao, Y.; Simonetto, D.A.; Yaqoob, U.; et al. Mechanical Stretch Increases Expression of CXCL1 in Liver Sinusoidal Endothelial Cells to Recruit Neutrophils, Generate Sinusoidal Microthombi, and Promote Portal Hypertension. Gastroenterology 2019, 157, 193–209.e9.
  59. van der Windt, D.J.; Sud, V.; Zhang, H.; Varley, P.R.; Goswami, J.; Yazdani, H.O.; Tohme, S.; Loughran, P.; O’Doherty, R.M.; Minervini, M.I.; et al. Neutrophil Extracellular Traps Promote Inflammation and Development of Hepatocellular Carcinoma in Nonalcoholic Steatohepatitis. Hepatology 2018, 68, 1347–1360.
  60. Leppkes, M.; Knopf, J.; Naschberger, E.; Lindemann, A.; Singh, J.; Herrmann, I.; Stürzl, M.; Staats, L.; Mahajan, A.; Schauer, C.; et al. Vascular Occlusion by Neutrophil Extracellular Traps in COVID-19. EBioMedicine 2020, 58, 102925.
  61. Middleton, E.A.; He, X.-Y.; Denorme, F.; Campbell, R.A.; Ng, D.; Salvatore, S.P.; Mostyka, M.; Baxter-Stoltzfus, A.; Borczuk, A.C.; Loda, M.; et al. Neutrophil Extracellular Traps Contribute to Immunothrombosis in COVID-19 Acute Respiratory Distress Syndrome. Blood 2020, 136, 1169–1179.
  62. Noguchi, D.; Kuriyama, N.; Ito, T.; Fujii, T.; Kato, H.; Mizuno, S.; Sakurai, H.; Isaji, S. Antiapoptotic Effect by PAR-1 Antagonist Protects Mouse Liver Against Ischemia-Reperfusion Injury. J. Surg. Res. 2020, 246, 568–583.
  63. SenBanerjee, S.; Lin, Z.; Atkins, G.B.; Greif, D.M.; Rao, R.M.; Kumar, A.; Feinberg, M.W.; Chen, Z.; Simon, D.I.; Luscinskas, F.W.; et al. KLF2 Is a Novel Transcriptional Regulator of Endothelial Proinflammatory Activation. J. Exp. Med. 2004, 199, 1305–1315.
  64. Nayak, L.; Lin, Z.; Jain, M.K. “Go With the Flow”: How Krüppel-Like Factor 2 Regulates the Vasoprotective Effects of Shear Stress. Antioxid. Redox Signal. 2011, 15, 1449–1461.
  65. Lin, Z.; Hamik, A.; Jain, R.; Kumar, A.; Jain, M.K. Kruppel-Like Factor 2 Inhibits Protease Activated Receptor-1 Expression and Thrombin-Mediated Endothelial Activation. Arterioscler. Thromb. Vasc. Biol. 2006, 26, 1185.
  66. Marrone, G.; Russo, L.; Rosado, E.; Hide, D.; García-Cardeña, G.; García-Pagán, J.C.; Bosch, J.; Gracia-Sancho, J. The Transcription Factor KLF2 Mediates Hepatic Endothelial Protection and Paracrine Endothelial–Stellate Cell Deactivation Induced by Statins. J. Hepatol. 2013, 58, 98–103.
  67. Marrone, G.; Maeso-Díaz, R.; García-Cardena, G.; Abraldes, J.G.; García-Pagán, J.C.; Bosch, J.; Gracia-Sancho, J. KLF2 Exerts Antifibrotic and Vasoprotective Effects in Cirrhotic Rat Livers: Behind the Molecular Mechanisms of Statins. Gut 2015, 64, 1434–1443.
  68. Marrone, G.; Shah, V.H.; Gracia-Sancho, J. Sinusoidal Communication in Liver Fibrosis and Regeneration. J. Hepatol. 2016, 65, 608–617.
  69. Atkins, G.B.; Jain, M.K. Role of Krüppel-Like Transcription Factors in Endothelial Biology. Circ. Res. 2007, 100, 1686–1695.
  70. Kamel, N.M.; El-Tanbouly, D.M.; Abdallah, D.M.; Sayed, H.M. PAR1, a Therapeutic Target for Remote Lung Injury Associated with Hind Limb Ischemia/Reperfusion: ERK5/KLF2-Dependent Lung Capillary Barrier Preservation. Chem. Biol. Interact. 2022, 354, 109809.
  71. Chen, T.; Shi, Z.; Zhao, Y.; Meng, X.; Zhao, S.; Zheng, L.; Han, X.; Hu, Z.; Yao, Q.; Lin, H.; et al. LncRNA Airn Maintains LSEC Differentiation to Alleviate Liver Fibrosis via the KLF2-ENOS-SGC Pathway. BMC Med. 2022, 20, 335.
  72. Tripodi, A.; Primignani, M.; Mannucci, P.M.; Caldwell, S.H. Changing concepts of cirrhotic coagulopathy. Am. J. Gastroenterol. 2017, 112, 274–281.
  73. Tripodi, A.; Primignani, M.; Chantarangkul, V.; Dell’Era, A.; Clerici, M.; de Franchis, R.; Colombo, M.; Mannucci, P.M. An imbalance of pro- vs anti-coagulation factors inplasma from patients with cirrhosis. Gastroenterology 2009, 137, 2105–2111.
  74. Tripodi, A.; Primignani, M.; Lemma, L.; Chantarangkul, V.; Dell’Era, A.; Iannuzzi, F.; Aghemo, A.; Mannucci, P.M. Detection of the imbalance of procoagulant versus anticoagulant factors in cirrhosis by a simple laboratory method. Hepatology 2010, 52, 249–255.
  75. Tripodi, A.; Chantarangkul, V.; Primignani, M.; Clerici, M.; Dell’Era, A.; Aghemo, A.; Mannucci, P.M. Thrombin generation in plasma from patients with cirrhosis supplemented with normal plasma: Considerations on the efficacy of treatment with fresh-frozen plasma. Intern. Emerg. Med. 2012, 7, 139–144.
  76. Tripodi, A.; Salerno, F.; Chantarangkul, V.; Clerici, M.; Cazzaniga, M.; Primignani, M.; Mannuccio Mannucci, P. Evidence of normal thrombin generation in cirrhosis despite abnormal conventional coagulation tests. Hepatology 2005, 41, 553–558.
  77. Sinegre, T.; Duron, C.; Lecompte, T.; Pereira, B.; Massoulier, S.; Lamblin, G.; Abergel, A.; Lebreton, A. Increased factor VIII plays a significant role in plasma hypercoagulability phenotype of patients with cirrhosis. J. Thromb Haemost. 2018, 16, 1132–1140.
  78. Zou, Z.; Yan, X.; Li, C.; Li, X.; Ma, X.; Zhang, C.; Ju, S.; Tian, J.; Qi, X. von Willebrand factor as a biomarker of clinically significant portal hypertension and severe portal hypertension: A systematic review and meta-analysis. BMJ Open 2019, 9, e025656.
  79. Shahani, T.; Covens, K.; Lavend’homme, R.; Jazouli, N.; Sokal, E.; Peerlinck, K.; Jacquemin, M. Human liver sinusoidal endothelial cells but not hepatocytes contain factor VIII. J. Thromb Haemost. 2014, 12, 36–42.
  80. Tornai, I.; Hársfalvi, J.; Boda, Z.; Udvardy, M.; Pfliegler, G.; Rak, K. Endothelium releases more von Willebrand factor and tissue-type plasminogen activator upon venous occlusion in patients with liver cirrhosis than in normals. Haemostasis 1993, 23, 58–64.
  81. Bernardo, A.; Ball, C.; Nolasco, L.; Moake, J.F.; Dong, J.F. Effects of inflammatory cytokines on the release and cleavage of the endothelial cell-derived ultralarge von Willebrand factor multimers under flow. Blood 2004, 104, 100–106.
  82. La Mura, V.; Reverter, J.C.; Flores-Arroyo, A.; Raffa, R.; Reverter, E.; Seijo, S.; Albrades, J.G.; Bosch, J.; Garcia-Pagan, J.C. Von Willebrand factor levels predict clinical outcome in patients with cirrhosis and portal hypertension. Gut 2011, 60, 1133–1138.
  83. Ferlitsch, M.; Reiberger, T.; Hoke, M.; Salzl, P.; Schwengerer, B.; Ulbrich, G.; Payer, B.A.; Trauner, M.; Peck-Radosavljevic, M.; Ferlitsch, A. von Willebrand factor as new noninvasive predictor of portal hypertension, decompensation and mortality in patients with liver cirrhosis. Hepatology 2012, 56, 1439–1447.
  84. Maieron, A.; Salzl, P.; Peck-Radosavljevic, M.; Trauner, M.; Hametner, S.; Schöfl, R.; Ferenci, P. Ferlitsch Von Willebrand Factor as a new marker for non-invasive assessment of liver fibrosis and cirrhosis in patients with chronic hepatitis C. Aliment. Pharmacol. Ther. 2014, 39, 331–338.
  85. Lenting, P.J.; Christophe, O.D.; von Denis, C.V. Willebrand factor biosynthesis, secretion, and clearance: Connecting the far ends. Blood 2015, 125, 2019–2028.
  86. Pan, J.; Dinh, T.T.; Rajaraman, A.; Lee, M.; Scholz, A.; Czupalla, C.J.; Kiefel, H.; Zhu, L.; Xia, L.; Morser, J.; et al. Patterns of expression of factor VIII and von Willebrand factor by endothelial cell subsets in vivo. Blood 2016, 128, 104–109.
  87. Zheng, X.; Chung, D.; Takayama, T.K.; Majerus, E.M.; Sadler, J.E.; Fujikawa, K. Structure of von Willebrand factor-cleaving protease (ADAMTS13), a metalloprotease involved in thrombotic thrombocytopenic purpura. J. Biol. Chem. 2001, 276, 41059–41063.
  88. Soejima, K.; Mimura, N.; Hirashima, M.; Maeda, H.; Hamamoto, T.; Nakagaki, T.; Nozaki, C. A novel human metalloprotease synthesized in the liver and secreted into the blood: Possibly, the von Willebrand factor-cleaving protease? J. Biochem. 2001, 130, 475–480.
  89. Uemura, M.; Tatsumi, K.; Matsumoto, M.; Fujimoto, M.; Matsuyama, T.; Ishikawa, M.; Iwamoto, T.A.; Mori, T.; Wanaka, A.; Fukui, H.; et al. Localization of ADAMTS13 to the stellate cells of human liver. Blood 2005, 106, 922–924.
  90. Suzuki, M.; Murata, M.; Matsubara, Y.; Uchida, T.; Ishihara, H.; Shibano, T.; Ashida, S.; Soejima, K.; Okada, Y.; Ikeda, Y. Detection of von Willebrand factor-cleaving protease (ADAMTS-13) in human platelets. Biochem. Biophys. Res. Commun. 2004, 313, 212–216.
  91. Zhou, W.; Inada, M.; Lee, T.P.; Benten, D.; Lyubsky, S.; Bouhassira, E.E.; Gupta, S.; Tsai, H.M. ADAMTS13 is expressed in hepatic stellate cells. Lab. Investig. 2005, 85, 780–788.
  92. Uemura, M.; Fujimura, Y.; Matsumoto, M.; Ishizashi, H.; Kato, S.; Matsuyama, T.; Isonishi, A.; Ishikawa, M.; Yagita, M.; Morioka, C.; et al. Comprehensive analysis of ADAMTS13 in patients with liver cirrhosis. Thromb. Haemost. 2008, 99, 1019–1029.
  93. Levy, G.G.; Nichols, W.C.; Lian, E.C.; Foroud, T.; McClintick, J.N.; McGee, B.M.; Yang, A.Y.; Siemieniak, D.R.; Stark, K.R.; Gruppo, R.; et al. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature. 2001, 413, 488–494.
  94. Kokame, K.; Matsumoto, M.; Soejima, K.; Yagi, H.; Ishizashi, H.; Funato, M.; Tamai, H.; Konno, M.; Kamide, K.; Kawano, Y.; et al. Mutations and common polymorphisms in ADAMTS13 gene responsible for von Willebrand factor-cleaving protease activity. Proc. Natl. Acad. Sci. USA 2002, 99, 11902–11907.
  95. Feys, H.B.; Canciani, M.T.; Peyvandi, F.; Deckmyn, H.; Vanhoorelbeke, K.; Mannucci, P.M. ADAMTS13 activity to antigen ratio in physiological and pathological conditions associated with an increased risk of thrombosis. Br. J. Haematol. 2007, 138, 534–540.
  96. Uemura, M.; Matsuyama, T.; Ishikawa, M.; Fujimoto, M.; Kojima, H.; Sakurai, S.; Ishii, S.; Toyohara, M.; Yamazaki, M.; Yoshiji, H.; et al. Decreased activity of plasma ADAMTS13 may contribute to the development of liver disturbance and multiorgan failure in patients with alcoholic hepatitis. Alcohol. Clin. Exp. Res. 2005, 29 (Suppl. 12), 264S–271S.
  97. Matsuyama, T.; Uemura, M.; Ishikawa, M.; Matsumoto, M.; Ishizashi, H.; Kato, S.; Morioka, C.; Fujimoto, M.; Kojima, H.; Yoshiji, H.; et al. Increased von Willebrand factor over decreased ADAMTS13 activity may contribute to the development of liver disturbance and multiorgan failure in patients with alcoholic hepatitis. Alcohol. Clin. Exp. Res. 2007, 31 (Suppl. 1), S27–S35.
  98. Wanless, I.R.; Wong, F.; Blendis, L.M.; Greig, P.; Heathcote, E.J.; Levy, G. Hepatic and portal vein thrombosis in cirrhosis: Possible role in development of parenchymal extinction and portal hypertension. Hepatology 1995, 21, 1238–1247.
  99. Moake, J.L. Thrombotic microangiopathies. N. Engl. J. Med. 2002, 347, 589–600.
  100. Fujimura, Y.; Matsumoto, M.; Yagi, H.; Yoshioka, A.; Matsui, T.; Titani, K. Von Willebrand factor-cleaving protease and Upshaw-Schulman syndrome. Int. J. Hematol. 2002, 75, 25–34.
  101. Furlan, M. von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome. Adv. Nephrol. Necker. Hosp. 2000, 30, 71–81.
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to : , , , , , ,
View Times: 406
Revisions: 2 times (View History)
Update Date: 06 Jul 2023
Video Production Service