The profile of platelet α‐granule released molecules affects postoperative liver regeneration

Abstract

Platelets promote liver regeneration through site-specific serotonin release from dense granules, triggering proliferative signaling in hepatocytes. However, the effects of factors derived from platelet a-granules on liver regeneration are unclear, because a-granules contain bioactive molecules with opposing functions. Because a-granule molecules are stored in separate compartments, it has been suggested that platelets selectively release their a-granule content dependent on the environmental stimulus. Therefore, we investigated the pattern of circulating a-granule molecules during liver regeneration in 157 patients undergoing partial hepatectomy. We measured plasma levels of a-granule-derived factors in the liver vein at the end of liver resection, as well as on the first postoperative day. We observed a rapid accumulation of platelets within the liver after induction of liver regeneration. Platelet count and P-selectin (a ubiquitous cargo of a-granules) were not associated with postoperative liver dysfunction. However, low plasma levels of vascular endothelial growth factor (VEGF), but high levels of thrombospondin 1 (TSP-1), predicted liver dysfunction after resection. Patients with an unfavorable postoperative a-granule release profile (high TSP-1/low VEGF) showed substantially worse postoperative clinical outcomes. The unfavorable postoperative a-granule release profile was associated with increased postoperative portal venous pressure and von Willebrand factor antigen levels as a marker for intrahepatic endothelial dysfunction. Conclusion: The postoperative profile of circulating platelet-derived factors correlates with the ability of the remnant liver to regenerate. Portal venous pressure and intrahepatic endothelial dysfunction might account for the selective granule release profile. Selective modulation of platelet a-granule release in patients may represent an attractive target for therapeutic interventions to improve liver regeneration and clinical outcomes after partial hepatectomy. (HEPATOLOGY 2016;63:1675-1688 P latelets are critically involved not only in hemostasis, but also in inflammation, wound healing and angiogenesis. Through release of their granule content, they orchestrate signal responses in a plethora of target cells, including hepatocytes. Platelets are potent inducers of liver regeneration (LR) after partial hepatectomy and platelet activation as well as granule release increase after liver resection.(1,2) Platelet activation results in the release of dense granules, followed by secretion of a-granule content.(3) Exocytosis of a-granules represents a highly regulated process, involving distinct packaging

Evidence against a role for platelet-derived molecules in liver regeneration after partial hepatectomy in humans

“…Our results contradict recent clinical studies that have suggested consumption of serotonin and VEGF following a partial hepatectomy in humans [15,16]. Importantly, these studies did not control for the effects of major abdominal oncological surgery on levels of these molecules in platelets and/or plasma.…”

“…However, as serotonin is a relevant platelet activator [20], the decreased functional capacity of serotonin deficient platelets, rather than a direct mitogenic effect of serotonin could explain the delay in liver regeneration in these mice. In addition, studies in humans have suggested consumption of platelet-derived serotonin [15] and release of other molecules (notably vascular endothelial growth factor) potentially driving platelet-mediated liver regeneration from platelets following a liver regeneration in humans [16]. Unfortunately, these studies did not control for effects of a major surgical procedure, and in our opinion these data thus not convincingly demonstrate a role for platelet-derived proteins in liver regeneration in humans [21].…”

“…Although there is broad consensus that platelets stimulate liver regenera- tion in animal models and likely also in humans, there is ongoing debate on the molecular mechanisms underlying platelet-mediated stimulation of liver regeneration [11,12]. Some studies suggest that local release of growth factors or angiogenic molecules stored within platelet alpha and dense granules are responsible for platelet-mediated liver regeneration [4,[13][14][15][16]. Even though it has been reported that platelet-derived growth factors stimulate hepatocyte proliferation in vitro [13,14,17], it has not yet been established whether platelet-derived growth factors also drive platelet-mediated liver regeneration in vivo [12].…”

“…Even though it has been reported that platelet-derived growth factors stimulate hepatocyte proliferation in vitro [13,14,17], it has not yet been established whether platelet-derived growth factors also drive platelet-mediated liver regeneration in vivo [12]. Animal studies and a single study in humans have demonstrated accumulation of platelets within the liver remnant rapidly following a partial liver resection [5,16,18]. Nevertheless, it has not been unequivocally demonstrated that platelet accumulation results in (selective) release of liver-directed growth factors, nor has it been demonstrated that platelet derived growth factors indeed drive platelet-mediated liver regeneration.…”

Plasma molecules predicting liver dysfunction following partial hepatectomy are not only derived from platelet α‐granules

“…(1) While we agree that these plasma biomarkers appear excellent predictors of outcome, we feel that not all the conclusions are justified based on the data. First, the authors conclude that the biomarker combination correlates with the ability of the liver remnant to regenerate.…”