Dualistic role of platelets in living donor liver transplantation: Are they harmful?

Abstract

Platelets are anucleate fragments mainly involved in hemostasis and thrombosis, and there is emerging evidence that platelets have other nonhemostatic potentials in inflammation, angiogenesis, regeneration and ischemia/reperfusion injury (I/R injury), which are involved in the physiological and pathological processes during living donor liver transplantation (LDLT). LDLT is sometimes associated with impaired regeneration and severe I/R injury, leading to postoperative complications and decreased patient survival. Recent studies have suggested that perioperative thrombocytopenia is associated with poor graft regeneration and postoperative morbidity in the short and long term after LDLT. Although it is not fully understood whether thrombocytopenia is the cause or result, increasing platelet counts are frequently suggested to improve posttransplant outcomes in clinical studies. Based on rodent experiments, previous studies have identified that platelets stimulate liver regeneration after partial hepatectomy. However, the role of platelets in LDLT is controversial, as platelets are supposed to aggravate I/R injury in the liver. Recently, a rat model of partial liver transplantation (LT) was used to demonstrate that thrombopoietin-induced thrombocytosis prior to surgery accelerated graft regeneration and improved the survival rate after transplantation. It was clarified that platelet-derived liver regeneration outweighed the associated risk of I/R injury after partial LT. Clinical strategies to increase perioperative platelet counts, such as thrombopoietin, thrombopoietin receptor agonist and platelet transfusion, may improve graft regeneration and survival after LDLT.

Keywords: Ischemia/reperfusion injury; Kupffer cell; Liver transplantation; Oxidative stress; Platelet; Regeneration.

Figure 1

Platelets and liver regeneration. Platelets translocate into the space of Disse and release insulin-like growth factor-1, hepatocyte growth factor, and vascular endothelial growth factor. The direct contact of platelets with liver sinusoidal endothelial cells (LSECs) results in the excretion of interleukin-6 (IL-6) from LSECs. In addition, the attachment of platelets activates Kupffer cells (KCs) and enhances the release of tumor necrosis factor-alpha and IL-6 from KCs to promote liver regeneration. Moreover, platelets are internalized into hepatocytes and trigger the functional transfer of messenger RNA stored in platelets, which stimulates hepatocyte proliferation. KCs: Kupffer cells; LSECs: Liver sinusoidal endothelial cells; IGF-1: Insulin-like growth factor-1; HGF: Hepatocyte growth factor; VEGF: Vascular endothelial growth factor; LSECs: Liver sinusoidal endothelial cells; IL-6: Interleukin-6; KCs: Kupffer cells; TNF-α: Tumor necrosis factor-alpha.

Figure 2

Platelets and ischemia/reperfusion injury. Liver sinusoidal endothelial cells (LSECs) express selectins and integrins to stimulate the interaction between platelets and LSECs, and platelets result in the excretion of interleukin-6 (IL-6) from LSECs. The generation of tumor necrosis factor-alpha, IL-6 and reactive oxygen species (ROS) from KCs is elevated after the cooperative effect between platelets and KCs. Furthermore, platelets can produce ROS independently and consequently aggravate ischemia/reperfusion injury. KCs: Kupffer cells; LSECs: Liver sinusoidal endothelial cells; IL-6: Interleukin-6; TNF-α: Tumor necrosis factor-alpha; ROS: Reactive oxygen species; I/R injury: Ischemia/reperfusion injury.

Figure 3

Platelets, liver regeneration and ischemia/reperfusion injury after partial liver transplantation. After accumulating in the liver graft, platelets excrete hepatocyte growth factor (HGF) and insulin-like growth factor-1 (IGF-1) and collaborate with KCs to increase the release of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). As a result, the serum levels of HGF, IGF-1, IL-6 and TNF-α increase under thrombocytosis, which consequently induces the phosphorylation of the ERK, Akt, STAT3 and nuclear factor-kappa B signaling pathways to promote liver regeneration (Cyclin D1). On the other hand, platelets do not aggravate in ischemia/reperfusion injury. The phosphorylated Akt pathway inhibits TNF-α-induced apoptosis and necrosis in the liver graft. KCs: Kupffer cells; HGF: Hepatocyte growth factor; IL-6: Interleukin-6; IGF-1: Insulin-like growth factor-1; TNF-α: Tumor necrosis factor-alpha; HGFR: HGF receptor; IGF1R: IGF-1 receptor; gp130: Glycoprotein 130; TNFR1: Tumor necrosis factor receptor; ERK: Extracellular signal-regulated kinase; STAT3: Signal transducer and activator of transcription 3; NF-κB: Nuclear factor-kappa B; Caspase: Cysteinyl aspartate specific proteinase; I/R injury: Ischemia/reperfusion injury.