Deficiency in Thrombopoietin Induction after Liver Surgery Is Associated with Postoperative Liver Dysfunction

<div><p>Background and Aims</p><p>Thrombopoietin (TPO) has been implicated in the process of liver regeneration and was found to correlate with hepatic function in patients with liver disease. With this investigation we aimed to determine if perioperative TPO levels were associated with postoperative outcome in patients undergoing liver resection.</p><p>Methods</p><p>Perioperative TPO was analyzed prior to liver resection as well as on the first and fifth postoperative day in 46 colorectal cancer patients with liver metastasis (mCRC) as well as 23 hepatocellular carcinoma patients (HCC). Serum markers of liver function within the first postoperative week were used to define liver dysfunction.</p><p>Results</p><p>While circulating TPO levels significantly increased one day after liver resection in patients without liver cirrhosis (mCRC) (P < 0.001), patients with underlying liver disease (HCC) failed to significantly induce TPO postoperatively. Accordingly, HCC patients had significantly lower TPO levels on POD1 and 5. Similarly, patients with major resections failed to increase circulating TPO levels. Perioperative dynamics of TPO were found to specifically predict liver dysfunction (AUC: 0.893, P < 0.001) after hepatectomy and remained an independent predictor upon multivariate analysis.</p><p>Conclusions</p><p>We here demonstrate that perioperative TPO dynamics are associated with postoperative LD. Postoperative TPO levels were found to be lowest in high-risk patients (HCC patients undergoing major resection) but showed an independent predictive value. Thus, a dampened TPO increase after liver resection reflects a poor capacity for hepatic recovery and may help to identify patients who require close monitoring or intervention for potential complications.</p></div

Perioperative fluctuations of platelet counts and circulating TPO in patients with major or minor resection.

<p>Plasma TPO levels were measured prior to surgery (PRE OP), on the first postoperative day (POD 1) and on POD 5. Circulating TPO levels are illustrated by boxplot in A. Patients were further divided in two groups undergoing major or minor liver resection (B). Comparably, platelet counts are illustrated for the entire collective (C) and for patients undergoing major or minor resection (D). * P < 0.05; ** P < 0.005.</p

Patient Demographics.

<p>ALT = alanine aminotransferase, ALP = alkaline phosphatase, AST = aspartate aminotransferase, CTx = chemotherapy, GGT = gamma-glutamyltransferase, HCC = hepatocellular carcinoma, LD = liver dysfunction, mCRC = metastatic colorectal cancer, PDR = plasma disappearance rate, PT = prothrombin time, RBC = red blood cells, R15 = retention rate after 15 min, SB = serum bilirubin.</p><p>* only patients with pringle included (20).</p><p>** only patients with intraoperative RBC included (6).</p><p>Patient Demographics.</p

Perioperative changes in circulating platelet counts and TPO in patients with or without underlying liver disease.

<p>Plasma TPO levels were measured prior to surgery (PRE OP), on the first postoperative day (POD 1) and on POD 5. Patients were further divided in groups with underlying liver disease (HCC) or without underlying liver disease (mCRC). Circulating TPO levels are illustrated by boxplot in A. Comparably, platelet counts are illustrated in B. * P < 0.05; ** P < 0.005.</p

Perioperative TPO dynamics predict postoperative LD.

<p>Pre- and postoperative TPO levels are illustrated to demonstrate perioperative TPO changes in patients with or without postoperative LD (A). To reflect perioperative TPO dynamics the ratio of pre- to postoperative TPO levels was calculated (postoperative TPO: preoperative TPO). B illustrates fold increase in plasma TPO according to tumor type and liver dysfunction. Further ROC analysis was performed for LD and absolute levels of TPO on POD 1 (C) as well as relative TPO increase (D). * P < 0.05; ** P < 0.005.</p

Predictors of LD after Hepatectomy.

<p>ALT = alanine aminotransferase, ALP = alkaline phosphatase, AST = aspartate aminotransferase, CTx = chemotherapy, GGT = gamma-glutamyltransferase, PDR = plasma disappearance rate, PT = prothrombin time, R15 = retention rate after 15 min, RBC = red blood cell, SB = serum bilirubin, TPO = thrombopoietin.</p><p>Predictors of LD after Hepatectomy.</p

Early prediction of postoperative liver dysfunction and clinical outcome using antithrombin III-activity

<div><p>Background and aims</p><p>Antithrombin III (ATIII) has been reported to be associated with liver pathologies and was shown to predict outcome in patients undergoing liver resection for hepatocellular carcinoma. We now aimed to assess whether perioperative ATIII-activity could predict postoperative outcome in patients without underlying liver disease, as well as in a routine clinical setting of patients undergoing hepatic resection.</p><p>Methods</p><p>ATIII-activity was evaluated preoperatively and on the first (POD1) and fifth day after liver resection in a retrospective evaluation cohort of 228 colorectal cancer patients with liver metastasis (mCRC). We further aimed to prospectively validate our results in a set of 177 consecutive patients undergoing hepatic resection.</p><p>Results</p><p>Patients developing postoperative liver dysfunction (LD) had a more pronounced postoperative decrease in ATIII-activity (P<0.001). ATIII-activity on POD1 significantly predicted postoperative LD (P<0.001, AUC = 84.4%) and remained independent upon multivariable analysis. A cut-off value of 61.5% ATIII-activity was determined using ROC analysis. This cut-off was vital to identify high-risk patients for postoperative LD, morbidity, severe morbidity and mortality (P<0.001, respectively) with a highly accurate negative predictive value of 97%, which could be confirmed for LD (P<0.001) and mortality (P = 0.014) in our independent validation cohort. Further, mCRC patients below our cut-off suffered from a significantly decreased overall survival (OS) at 1 and 3 years after surgery (P = 0.011, P = 0.025).</p><p>Conclusions</p><p>The routine laboratory parameter ATIII-activity on POD1 independently predicted postoperative LD and was associated with clinical outcome. Patients with a postoperative ATIII-activity <61.5% might benefit from close monitoring and timely initiation of supportive therapy.</p><p>Trial registration</p><p>ClinicalTrials.gov <a href="https://clinicaltrials.gov/ct2/show/NCT01700231" target="_blank">NCT01700231</a></p></div

Decision tree for postoperative risk stratification.

<p>Combination of ATIII-activity and SB values on POD1 allows highly specific discrimination of patients risk for postoperative LD.</p

Detail on postoperative thromboembolic incidences.

<p>Detail on postoperative thromboembolic incidences.</p

ATIII-activity on POD1 competes other markers in the prediction of postoperative LD.

<p>Predictive value of ATIII-activity, CRP, fibrinogen, SB, PT, AST, ALT and GGT on POD1 to predict postoperative LD using receiver operating characteristics (ROC) analysis was compared.</p