Platelet activation and increased tissue factor expression on monocytes in reperfusion injury following orthotopic liver transplantation

Esch, Jan Schulte Am; Jurk, Kerstin; Knoefel, Wolfram Trudo; Roeder, G; Voss, H. Fred; Tustas, R.; Schmelzle, Moritz; Krieg, Andreas; Eisenberger, Claus Ferdinand; Topp, Stefan A.; Rogiers, Xavier; Fischer, Lutz; Aken, Hugo Van; Kehrel, Beate E.

doi:10.3109/09537101003739897

Cited by 29 publications

(18 citation statements)

References 42 publications

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“…This may also explain why R does not appear to be sensitive to mild to moderate increases in PT INR [32]. Another potential reason is that tissue factor expression on monocytes leads to a shortened R, as seen in some patients with CLD [33]. By contrast, the correlation between platelet count and MA was strong (r=0.712) in this study.…”

Section: Discussionmentioning

confidence: 70%

Thromboelastographic Evaluation of Coagulation in Patients With Liver Disease

et al. 2017

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BackgroundThe aims of this study were to investigate the parameters of thromboelastography (TEG) for evaluating coagulopathy and to reveal an association with disease severity and/or transfusion requirement in patients with chronic liver disease (CLD) in a clinical laboratory setting.MethodsWe enrolled two groups of adult patients with cirrhotic (N=123) and non-cirrhotic liver disease (N=52), as well as 84 healthy controls. Reaction time (R), kinetic time (K), α-angle (α), maximal amplitude (MA), and coagulation index (CI) were measured with kaolin-activated citrated blood with the TEG 5000 system (Haemonetics Corporation, USA). Platelet count, prothrombin time international normalized ratio (PT INR), albumin, bilirubin, and creatinine were simultaneously measured. The CLD severity was calculated by using the Child-Pugh (C-P) and Model for End-stage Liver Disease (MELD) scores. Transfusion history was also reviewed.ResultsAll TEG parameters, PT INR, and platelet count in the cirrhotic group showed significant differences from those in other groups. At least one or more abnormal TEG parameters were identified in 17.3% and 44.7% of patients in the non-cirrhotic and cirrhotic group, respectively. Patients with cirrhotic disease had hypocoagulability. A weak correlation between R and PT INR (r=0.173) was noted. The TEG parameters could not predict CLD severity using the C-P and MELD scores. Patients with normal TEG parameters did not receive transfusion.ConclusionsClinical application of TEG measurements in CLD can be informative for investigating coagulopathy or predicting the risk of bleeding. Further studies are warranted.

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Section: Discussionmentioning

confidence: 70%

Thromboelastographic Evaluation of Coagulation in Patients With Liver Disease

et al. 2017

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“…Diannexin is a biosynthesized human recombinant homodimer of annexin V that exerts considerable hepatoprotection against IRI in our murine model (Fig.6Bi); its efficacy associated with reduced swelling and detachment of SECs from their basement membrane, decreased hepatic expression of pro-inflammatory ICAM-1, VCAM and MIP-2, and abrogated leukocyte and platelet adherence to SECs [9], [10]. To establish whether this protective action involves attenuation of MP release, we injected mice with Diannexin (1 mg/kg), 5 min prior to hepatic ischemia and measured MP production during reperfusion.…”

Section: Resultsmentioning

confidence: 98%

“…These adhere to SECs that express adhesion molecules (E-selectin, P-selectin, ICAM-1, VCAM-1) and secrete chemokines [5]–[8] in response to hypoxia, oxidative stress, and tumor necrosis factor-α (TNF) [8]. Platelets are essential for hepatic IRI [9]; platelet clumps adhere to damaged SECs during the first 20 min of post-ischemic reperfusion [10]. The factors linking early SEC injury to inflammatory cell recruitment and platelet activation, with resultant microcirculatory impairment and hepatocyte injury have not been fully clarified.…”

Section: Introductionmentioning

confidence: 99%

Microparticles Mediate Hepatic Ischemia-Reperfusion Injury and Are the Targets of Diannexin (ASP8597)

et al. 2014

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Background & AimsIschemia–reperfusion injury (IRI) can cause hepatic failure after liver surgery or transplantation. IRI causes oxidative stress, which injures sinusoidal endothelial cells (SECs), leading to recruitment and activation of Kupffer cells, platelets and microcirculatory impairment. We investigated whether injured SECs and other cell types release microparticles during post-ischemic reperfusion, and whether such microparticles have pro-inflammatory, platelet-activating and pro-injurious effects that could contribute to IRI pathogenesis.MethodsC57BL6 mice underwent 60 min of partial hepatic ischemia followed by 15 min–24 hrs of reperfusion. We collected blood and liver samples, isolated circulating microparticles, and determined protein and lipid content. To establish mechanism for microparticle production, we subjected murine primary hepatocytes to hypoxia-reoxygenation. Because microparticles express everted phosphatidylserine residues that are the target of annexin V, we analyzed the effects of an annexin V-homodimer (Diannexin or ASP8597) on post-ischemia microparticle production and function.ResultsMicroparticles were detected in the circulation 15–30 min after post-ischemic reperfusion, and contained markers of SECs, platelets, natural killer T cells, and CD8+ cells; 4 hrs later, they contained markers of macrophages. Microparticles contained F2-isoprostanes, indicating oxidative damage to membrane lipids. Injection of mice with TNF-α increased microparticle formation, whereas Diannexin substantially reduced microparticle release and prevented IRI. Hypoxia-re-oxygenation generated microparticles from primary hepatocytes by processes that involved oxidative stress. Exposing cultured hepatocytes to preparations of microparticles isolated from the circulation during IRI caused injury involving mitochondrial membrane permeability transition. Microparticles also activated platelets and induced neutrophil migration in vitro. The inflammatory properties of microparticles involved activation of NF-κB and JNK, increased expression of E-selectin, P-selectin, ICAM-1 and VCAM-1. All these processes were blocked by coating microparticles with Diannexin.ConclusionsFollowing hepatic IRI, microparticles circulate and can be taken up by hepatocytes, where they activate signaling pathways that mediate inflammation and hepatocyte injury. Diannexin prevents microparticle formation and subsequent inflammation.

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“…Abundant evidence supports a critical role for platelets in the thrombogenic and inflammatory responses to I/R, wherein their interaction with leukocytes, lymphocytes, and endothelial cells acts to promote injury (Barrabés et al, 2010; Esch et al, 2010; Khandoga et al, 2002, 2006; Massberg et al, 1999; Nakano et al, 2008; Park et al, 2010; Peters et al, 1999; Tailor et al, 2005; Yilmaz and Granger, 2008; Zhao et al, 2009). In the absence of insult or injury, platelets circulate in an inactive state, owing to the presence of inhibitory factors such as nitric oxide and prostacyclin.…”

Section: Mechanisms Underlying I/r Injurymentioning

confidence: 99%

Cell Biology of Ischemia/Reperfusion Injury

Kalogeris

Baines

Krenz

et al. 2012

International Review of Cell and Molecular Biology

1,751

1,547

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Disorders characterized by ischemia/reperfusion (I/R), such as myocardial infarction, stroke, and peripheral vascular disease, continue to be among the most frequent causes of debilitating disease and death. Tissue injury and/or death occur as a result of the initial ischemic insult, which is determined primarily by the magnitude and duration of the interruption in the blood supply, and then subsequent damage induced by reperfusion. During prolonged ischemia, ATP levels and intracellular pH decrease as a result of anaerobic metabolism and lactate accumulation. As a consequence, ATPase-dependent ion transport mechanisms become dysfunctional, contributing to increased intracellular and mitochondrial calcium levels (calcium overload), cell swelling and rupture, and cell death by necrotic, necroptotic, apoptotic, and autophagic mechanisms. Although oxygen levels are restored upon reperfusion, a surge in the generation of reactive oxygen species occurs and proinflammatory neutrophils infiltrate ischemic tissues to exacerbate ischemic injury. The pathologic events induced by I/R orchestrate the opening of the mitochondrial permeability transition pore, which appears to represent a common end-effector of the pathologic events initiated by I/R. The aim of this treatise is to provide a comprehensive review of the mechanisms underlying the development of I/R injury, from which it should be apparent that a combination of molecular and cellular approaches targeting multiple pathologic processes to limit the extent of I/R injury must be adopted to enhance resistance to cell death and increase regenerative capacity in order to effect long-lasting repair of ischemic tissues.

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Platelet activation and increased tissue factor expression on monocytes in reperfusion injury following orthotopic liver transplantation

Cited by 29 publications

References 42 publications

Thromboelastographic Evaluation of Coagulation in Patients With Liver Disease

Thromboelastographic Evaluation of Coagulation in Patients With Liver Disease

Microparticles Mediate Hepatic Ischemia-Reperfusion Injury and Are the Targets of Diannexin (ASP8597)

Cell Biology of Ischemia/Reperfusion Injury

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