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.

Responses of hepatic sinusoidal cells to liver ischemia–reperfusion injury

“…Although the sequestration of platelets in hepatic sinusoids contributes to the progression of liver IRI (Teoh et al, 2007), platelet-derived pro-angiogenic mediators, including HGF, insulin-growth factor-1, and VEGF, contribute to the proliferation and regeneration of LSECs, leading to liver repair and regeneration. During liver regeneration after partial hepatectomy, direct contact of platelets with LSECs triggers the Frontiers in Cell and Developmental Biology frontiersin.org production of IL-6 (a key hepatocyte mitogen) from LSECs (Liang et al, 2022;Morris and Chauhan, 2022). Accumulation of platelets in hepatic sinusoids mitigates LSEC damage and helps regenerate damaged LSECs, resulting in liver regeneration (Meyer et al, 2015).…”

Role of the immune system in liver transplantation and its implications for therapeutic interventions

“…Additionally, other innate immune cells, including NKT cells, especially the Valpha14 NKT cell subtype, have been recognized for their role in immune tolerance following infusion 208 . In IRI, platelets are influenced by the inflammatory mediators released by KCs, resulting in the release of IL‐6, platelet‐activating factors, growth factors, TGF‐β, and other cytokines that contribute to the advancement of inflammation 209–211 . Peritoneal macrophages with the F4/80 hi GATA6 + LMP phenotype have been observed to migrate to the injury site and contribute to liver repair in experimental models of acute liver injury 212 …”

The roles of liver sinusoidal endothelial cells in liver ischemia/reperfusion injury

“…Platelets induce increased IL-6 expression in LSECs and interact with KCs to promote KCs release of TNF-α, IL-6, and ROS. 43 In addition, KCs play a key role in platelet activation. 44 TNF-α can induce upregulated P-selectin expression in LSECs and thus enhance platelet activation and adhesion.…”