Hepatocyte tissue factor activates the coagulation cascade in mice

Sullivan, Bradley P.; Kopec, Anna K.; Joshi, Nikita; Cline, Holly; Brown, Juliette A.; Bishop, Stephen H.; Kassel, Karen M.; Rockwell, Cheryl E.; Mackman, Nigel; Luyendyk, James P.

doi:10.1182/blood-2012-09-455436

Cited by 64 publications

(68 citation statements)

References 33 publications

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“…These observations suggest that intra-sinusoidal activation of hemostasis may lead to a secondary ischemic injury. The recent observation that acute liver injury may de-encrypt hepatocyte-derived tissue factor 31 provides a plausible mechanism by which such injury generates thrombin. In turn, thrombin generation may activate platelets and generate platelet microparticles; alternatively, platelet activation in patients with ALF might ensue via inflammatory mediators, which is perhaps more consistent with the data presented herein.…”

Section: Discussionmentioning

confidence: 99%

Thrombocytopenia Is Associated With Multi-organ System Failure in Patients With Acute Liver Failure

Stravitz

Ellerbe

Durkalski

et al. 2016

Clinical Gastroenterology and Hepatology

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Background & Aims Acute liver failure (ALF) is a syndrome characterized by an intense systemic inflammatory response (SIRS) and multi-organ system failure (MOSF). Platelet-derived microparticles increase in proportion to the severity of the SIRS and MOSF, and are associated with poor outcome. We investigated whether patients with ALF develop thrombocytopenia in proportion to the SIRS, MOSF, and poor outcome. Methods In a retrospective study, we collected data on post-admission platelet counts of 1598 patients included in the ALF Study Group Registry from 1998 through October, 2012. We investigated correlations between platelet counts and clinical features of ALF, laboratory test results, and outcomes. Of the patients studied, 752 (47%) survived without liver transplantation, 390 (24%) received liver transplants, and 517 (32%) died. Results In patients with SIRS, platelet counts decreased 2–7 days after admission, compared to patients without SIRS (P≤.001). Patients with abnormal levels of creatinine, phosphate, lactate, or bicarbonate had significantly lower platelet counts than patients with normal levels of these laboratories (all P≤.001). The decrease in platelets during days 1–7 after admission was proportional to the grade of hepatic encephalopathy and requirement for vasopressor and renal replacement therapy. Although platelet numbers decreased after admission in the overall population, platelets were significantly lower 2–7 days after admission in patients with outcomes of death or liver transplantation than in patients who made spontaneous recoveries and survived. In contrast, international normalized ratios over time were not associated with SIRS, laboratory test results associated with poor outcomes, grade of hepatic encephalopathy, or requirement for renal replacement therapy. Conclusions The development of thrombocytopenia in patients with ALF is associated with development of MOSF and poor outcome. We speculate that SIRS-induced activation of platelets, yielding microparticles, results in clearance of platelet remnants and subsequent thrombocytopenia.

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Section: Discussionmentioning

confidence: 99%

Thrombocytopenia Is Associated With Multi-organ System Failure in Patients With Acute Liver Failure

Stravitz

Ellerbe

Durkalski

et al. 2016

Clinical Gastroenterology and Hepatology

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“…12,13 Generation of the coagulation protease thrombin occurs rapidly after administration of a hepatotoxic dose of APAP to mice, and this procoagulant response is tissue factor-dependent. 14,15 Coinciding with coagulation cascade activation in clinical APAP-induced liver damage is a decrease in blood platelet concentration, and it has been suggested that platelets contribute to acute liver failure. 16 Although some molecules capable of affecting platelet function have been investigated in experimental APAP hepatotoxicity, the role of platelets in APAP-induced liver damage, particularly the link to coagulation, has not been directly investigated.…”

Section: Introductionmentioning

confidence: 99%

Platelets and protease-activated receptor-4 contribute to acetaminophen-induced liver injury in mice

Miyakawa¹,

Joshi

Sullivan³

et al. 2015

Blood

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Key Points• Platelets and PAR-4 contribute to the progression of APAPinduced liver injury in mice through independent pathways.Acetaminophen (APAP)-induced liver injury in humans is associated with robust coagulation cascade activation and thrombocytopenia. However, it is not known whether coagulation-driven platelet activation participates in APAP hepatotoxicity. Here, we found that APAP overdose in mice caused liver damage accompanied by significant thrombocytopenia and accumulation of platelets in the liver. These changes were attenuated by administration of the direct thrombin inhibitor lepirudin. Platelet depletion with an anti-CD41 antibody also significantly reduced APAP-mediated liver injury and thrombin generation, indicated by the concentration of thrombin-antithrombin (TAT) complexes in plasma. Compared with APAP-treated wild-type mice, biomarkers of hepatocellular and endothelial damage, plasma TAT concentration, and hepatic platelet accumulation were reduced in mice lacking protease-activated receptor (PAR)-4, which mediates thrombin signaling in mouse platelets. However, selective hematopoietic cell PAR-4 deficiency did not affect APAP-induced liver injury or plasma TAT levels. These results suggest that interconnections between coagulation and hepatic platelet accumulation promote APAP-induced liver injury, independent of platelet PAR-4 signaling. Moreover, the results highlight a potential contribution of nonhematopoietic cell PAR-4 signaling to APAP hepatotoxicity. (Blood. 2015;126(15):1835-1843 Introduction Acetaminophen (APAP) hepatotoxicity is the leading cause of druginduced liver injury and acute liver failure in the United States and other developed countries.1-4 Even though APAP hepatotoxicity has been recognized for more than 50 years, the main treatment options for overdose have been limited to early treatment with N-acetylcysteine and liver transplantation in the most severe cases. Many studies have been conducted to understand the mechanisms of APAP hepatotoxicity and to seek alternative therapies. It is commonly understood from early studies in murine models that APAP overdose leads to excessive production of the reactive metabolite, N-acetyl-p-benzoquinoneimine (NAPQI), and consequent depletion of hepatic glutathione (GSH), which is responsible for detoxifying NAPQI. This depletion of GSH permits NAPQI binding to cellular proteins, and this initiating event is followed by a myriad of cellular and molecular events involving parenchymal and nonparenchymal cells that ultimately determine the severity of liver damage. 5-10Evidence supports a role for numerous mediators in the pathogenesis of APAP-induced liver injury, including nitric oxide (NO) and peroxynitrite formation, oxidative stress, mitochondrial injury, alteration in hepatic blood flow, and the innate immune response. [8][9][10][11] APAP overdose is associated with activation of the coagulation cascade in mice and in humans.12-14 Indeed, consumptive coagulopathy is one of the major clinical signs in acute liver failure from AP...

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“…In steatohepatitis induced by a diet deficient in methionine and choline or Western diet-induced hepatic steatosis, TF-dependent thrombin generation and PAR1 signaling drive macrophage and neutrophil accumulation and hepatic inflammation (41;42). Emerging evidence further indicates that hepatotoxic injury may upregulate TF in hepatocytes (43). While these data underscore the importance of TF-initiated pathologies in various aspects of the metabolic syndrome, much remains to be elucidated about cell-type specific roles of TF and its signaling receptors in regulating inflammation and metabolism.…”

Section: Inflammatory Tf-par2 Signaling In Hepatic Gluconeogenesis Anmentioning

confidence: 99%

Tissue factor pathways linking obesity and inflammation

Ruf¹,

Samad²

2015

Hamostaseologie

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Obesity is a major cause for a spectrum of metabolic syndrome-related diseases that include insulin resistance, type 2 diabetes, and steatosis of the liver. Inflammation elicited by macrophages and other immune cells contributes to the metabolic abnormalities in obesity. In addition, coagulation activation following tissue factor (TF) upregulation in adipose tissue is frequently found in obese patients and particularly associated with diabetic complications. Genetic and pharmacological evidence indicates that TF makes significant contributions to the development of the metabolic syndrome by signaling through G protein-coupled protease activated receptors (PARs). Adipocyte TF–PAR2 signaling contributes to diet-induced obesity by decreasing metabolism and energy expenditure, whereas hematopoietic TF–PAR2 signaling is a major cause for adipose tissue inflammation, hepatic steatosis and inflammation, as well as insulin resistance. In the liver of mice on a high fat diet, PAR2 signaling increases transcripts of key regulators of gluconeogenesis, lipogenesis and inflammatory cytokines. Increased markers of hepatic gluconeogenesis correlate with decreased activation of AMP-activated protein kinase (AMPK), a known regulator of these pathways and a target for PAR2 signaling. Clinical markers of a TF-induced prothrombotic state may thus indicate a risk in obese patient for developing complications of the metabolic syndrome.

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Hepatocyte tissue factor activates the coagulation cascade in mice

Abstract: Key Points Mouse hepatocytes express cell surface tissue factor. Hepatocyte tissue factor activates the coagulation cascade in mice.

Cited by 64 publications

References 33 publications

Thrombocytopenia Is Associated With Multi-organ System Failure in Patients With Acute Liver Failure

Thrombocytopenia Is Associated With Multi-organ System Failure in Patients With Acute Liver Failure

Platelets and protease-activated receptor-4 contribute to acetaminophen-induced liver injury in mice

Tissue factor pathways linking obesity and inflammation

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