Plasma molecules predicting liver dysfunction following partial hepatectomy are not only derived from platelet α‐granules
Authors: Ton Lisman, Robert J. Porte
Journal: Hepatology (2016)

Potential conflict of interest: Nothing to report. Author names in bold denote shared co‐first authorship. To the Editor: With great interest we read the recent paper by Starlinger and coworkers in which it was demonstrated that a combination of levels of two plasma proteins (vascular endothelial growth factor [VEGF] and thrombospondin‐1 [TSP‐1]) on day 1 after a partial liver resection is highly predictive of postoperative liver dysfunction, morbidity, and duration of hospitalization.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. However, the endpoints are related to liver function, which does not necessarily correlate with the ability to regenerate. This would require studies employing analyses of recovery of liver volume, for example, using computed tomography. Second, the authors state that levels of VEGF and TSP‐1 (and other biomarkers assessed) reflect "the profile of platelet α‐granule released molecules." We do not agree with this interpretation. Whereas plasma levels of TSP‐1 and platelet factor 4 reflect platelet activation (and thus α‐granule release), changes in plasma levels of VEGF and fibrinogen likely also reflect production or release from sources other than platelets. Fibrinogen is synthesized by the liver, and synthesis rapidly increases following partial hepatectomy as part of an acute phase response.2 VEGF is also produced by the liver, and VEGF production by the liver profoundly increases as a response to partial hepatectomy.3 Moreover, VEGF can not only be released by platelets but also be actively taken up by platelets from the extracellular environment.4 Indeed, we have observed a selective increase in VEGF within platelets (without an increase in plasma) at 5 days after partial hepatectomy in humans, which is suggestive of platelet uptake of VEGF produced by the regenerating liver (Fig. 1).Figure 1: Citrated blood from 17 adult patients undergoing (extended) partial hepatectomy and 24 healthy individuals (controls) was processed to platelet‐rich and platelet‐poor plasma. Characteristics of patients and controls have been reported.5 The study protocol was approved by the local medical ethical committee, and informed consent was obtained from each subject before inclusion in the study. VEGF levels were measured by enzyme‐linked immunosorbent assay (Duoset; R&D Systems, Abingdon, UK) in plasma (A) and in platelet‐rich plasma that had been freeze‐thawed thrice prior to analysis. VEGF levels in platelets were obtained by subtracting VEGF levels in platelet‐poor plasma from levels in corresponding platelet‐rich plasma samples, and platelet VEGF levels were corrected for the platelet count in the platelet‐rich plasma (B). The higher preoperative levels of VEGF in platelets (but not in plasma) compared to controls is consistent with the reported selective increase in VEGF in platelets from patients with colorectal cancer.6 Bars represent means; error bars indicate standard error of the mean. *P < 0.01. Abbreviations: Pre‐OP, preoperative; POD, postoperative day.Rather than a result of selective α‐granule release, the decrease in VEGF and fibrinogen in patients with postoperative liver dysfunction likely reflects a poor regenerative response and decreased hepatic synthesis of these molecules. As stated by the authors, the increase in TSP‐1 likely reflects platelet activation. Enhanced platelet activation in patients with postoperative liver dysfunction appears plausible as platelets are likely to be more activated by both a damaged liver and elevated hepatic venous pressure gradients. Thus, although we congratulate the authors on their findings, we question whether the results reflect an "α‐granule release profile" and anticipate that a combination of enhanced platelet activation and decreased hepatic synthesis of fibrinogen and VEGF explains these findings.