Targeting Platelet Migration in the Postischemic Liver by Blocking Protease-Activated Receptor 4

Mende, Konstantin; Reifart, Jörg; Rosentreter, Dirk; Manukyan, Davit; Mayr, Doris; Krombach, Fritz; Rentsch, Markus; Khandoga, Andrej

doi:10.1097/01.tp.0000437430.89485.a0

Cited by 20 publications

(19 citation statements)

References 32 publications

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“…Platelets have been implicated in worsening ischaemia-reperfusion injury, which accounts for 10% of early graft dysfunction and predisposes to acute and chronic rejection. The suggested mechanism is via platelet sequestration in the hepatic microvasculature, where up regulation of proinflammatory endothelial injury and necrotic apoptosis could be exacerbated by platelet transfusion [22] . The vasoactive effects of platelets may cause other negative systemic consequences such as pulmonary hypertension and haemodynamic disturbance.…”

Section: Drivers For Transfusion-free Transplantationmentioning

confidence: 99%

Reducing transfusion requirements in liver transplantation

Donohue

Mallett

2015

WJT

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Liver transplantation (LT) was historically associated with massive blood loss and transfusion. Over the past two decades transfusion requirements have reduced dramatically and increasingly transfusionfree transplantation is a reality. Both bleeding and transfusion are associated with adverse outcomes in LT. Minimising bleeding and reducing unnecessary transfusions are therefore key goals in the perioperative period. As the understanding of the causes of bleeding has evolved so too have techniques to minimize or reduce the impact of blood loss. Surgical "piggyback" techniques, anaesthetic low central venous pressure and haemodilution strategies and the use of autologous cell salvage, point of care monitoring and targeted correction of coagulopathy, particularly through use of factor concentrates, have all contributed to declining reliance on allogenic blood products. Pre-emptive management of preoperative anaemia and adoption of more restrictive transfusion thresholds is increasingly common as patient blood management (PBM) gains momentum. Despite progress, increasing use of marginal grafts and transplantation of sicker recipients will continue to present new challenges in bleeding and transfusion management. Variation in practice across different centres and within the literature demonstrates the current lack of clear transfusion guidance. In this article we summarise the causes and predictors of bleeding and present the evidence for a variety of PBM strategies in LT. Core tip: Liver transplantation (LT) was historically associated with massive blood loss. Many factors have contributed to the decline in bleeding and transfusion in the past two decades including refinement of surgical techniques, anaesthetic management and the use of point of care guided goal-directed haemostatic therapies. Increasing awareness of the adverse associations of allogenic transfusion has driven the quest for transfusion-free transplantation. Increasing use of marginal grafts and transplantation of sicker recipients will continue to challenge perioperative care and transfusion practice. Inter-institutional variability suggests a current lack of clear guidance and limited application of the principles of patient blood management to LT.

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Section: Drivers For Transfusion-free Transplantationmentioning

confidence: 99%

Reducing transfusion requirements in liver transplantation

Donohue

Mallett

2015

WJT

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“…In addition, it has also been postulated that platelets are essential for the liver to regenerate properly following a partial liver resection (42). Platelet aggregation has been associated with microvascular perfusion defects, apoptotic cell death, vascular oxidative stress and an inflamed endothelium (43), all suggesting a pathophysiological connection between platelets and hepatocytes. In the present study, GalN induced OH • radicals in platelets; however, it did not cause platelet aggregation when analyzed alone or in collagen pretreated conditions.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of free radical generation in platelets and primary hepatocytes: A novel electron spin resonance study

et al. 2017

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Oxygen free radicals have been implicated in the pathogenesis of toxic liver injury and are thought to be involved in cardiac dysfunction in the cirrhotic heart. Therefore, direct evidence for the electron spin resonance (ESR) detection of how D‑galactosamine (GalN), an established experimental hepatotoxic substance, induced free radicals formation in platelets and primary hepatocytes is presented in the present study. ESR results demonstrated that GalN induced hydroxyl radicals (OH•) in a resting human platelet suspension; however, radicals were not produced in a cell free Fenton reaction system. The GalN‑induced OH• formation was significantly inhibited by the cyclooxygenase (COX) inhibitor indomethasin, though it was not affected by the lipoxygenase (LOX) or cytochrome P450 inhibitors, AA861 and 1‑aminobenzotriazole (ABT), in platelets. In addition, the present study demonstrated that baicalein induced semiquinone free radicals in platelets, which were significantly reduced by the COX inhibitor without affecting the formed OH•. In the mouse primary hepatocytes, the formation of arachidonic acid (AA) induced carbon‑centered radicals that were concentration dependently enhanced by GalN. These radicals were inhibited by AA861, though not affected by indomethasin or ABT. In addition, GalN did not induce platelet aggregation prior to or following collagen pretreatment in human platelets. The results of the present study indicated that GalN and baicalein may induce OH• by COX and LOX in human platelets. GalN also potentiated AA induced carbon‑centered radicals in hepatocytes via cytochrome P450. The present study presented the role of free radicals in the pathophysiological association between platelets and hepatocytes.

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“…Coagulation inhibition takes multiple forms, uncovering the complexity of this pathway. As a first example, in a mouse model of liver IRI, the Protease activated receptor (PAR)-4 pathway was targeted [65], while a clinical study showed that PAR-1 is expressed by DCs in DGF grafts and its activation may induce complement production and a Th1 bias [66]. Secondly, in a mouse model of hepatic IRI, recombinant human thrombomoduling was protective, and specifically this activity was brought through the N-terminal lectin-like domain 1 (D1) subunit, involving TLR4 signaling [67].…”

Section: Additives In Preservation Solution: Improve the Now Whilementioning

confidence: 99%

Barriers and Advances in Kidney Preservation

Steichen

Giraud

Bon

et al. 2018

BioMed Research International

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Despite the fact that a significant fraction of kidney graft dysfunctions observed after transplantation is due to ischemia-reperfusion injuries, there is still no clear consensus regarding optimal kidney preservation strategy. This stems directly from the fact that as of yet, the mechanisms underlying ischemia-reperfusion injury are poorly defined, and the role of each preservation parameter is not clearly outlined. In the meantime, as donor demography changes, organ quality is decreasing which directly increases the rate of poor outcome. This situation has an impact on clinical guidelines and impedes their possible harmonization in the transplant community, which has to move towards changing organ preservation paradigms: new concepts must emerge and the definition of a new range of adapted preservation method is of paramount importance. This review presents existing barriers in transplantation (e.g., temperature adjustment and adequate protocol, interest for oxygen addition during preservation, and clear procedure for organ perfusion during machine preservation), discusses the development of novel strategies to overcome them, and exposes the importance of identifying reliable biomarkers to monitor graft quality and predict short and long-term outcomes. Finally, perspectives in therapeutic strategies will also be presented, such as those based on stem cells and their derivatives and innovative models on which they would need to be properly tested.

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Targeting Platelet Migration in the Postischemic Liver by Blocking Protease-Activated Receptor 4

Abstract: Our in vivo data suggest PAR-4 as a potential target for future therapeutic strategies against platelet-mediated liver injury on transplantation.

Cited by 20 publications

References 32 publications

Reducing transfusion requirements in liver transplantation

Reducing transfusion requirements in liver transplantation

Mechanism of free radical generation in platelets and primary hepatocytes: A novel electron spin resonance study

Barriers and Advances in Kidney Preservation

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