The focus of our present study was to explore how plasma concentrations and de novo synthesis of two major hepatic export proteins were affected perioperatively by major abdominal surgery with and without a reduction in liver mass.
Following both major liver resections and pancreatic resections there was a dramatic increase in the de novo synthesis rate of fibrinogen on postoperative day 1, most pronounced in the pancreatectomy group with an intact liver mass. As far as we are aware, this is the first time this physiological response has been described. Postoperative levels (or change in levels) of plasma fibrinogen concentrations were not indicators for levels (or change in levels) of synthesis. On the contrary, plasma concentrations were marginally decreased (in all subjects undergoing hepatectomy) or unaltered (pancreatectomy) on postoperative day 1, which was in agreement with previous studies (12, 13, 25). At this time-point the plasma fibrinogen concentrations likely were on an upward trend, as their nadir, according to previous studies, is at the end of the operation (13, 26). On postoperative days 3–5 this increase in de novo synthesis was levelled off, but plasma concentration showed an overshoot compared to preoperative values in the pancreatectomy patients with the intact liver mass. The indirect biomarkers of fibrinogen utilization showed an activation on postoperative day 1 (TAT and soluble fibrin), and a more prolonged activation (D-dimer), where the difference between hepatectomy and pancreatectomy groups was equivocal. For coagulation competence, the global measures via tromboelastometry showed balanced coagulation for both groups of patients.
The concentrations of plasma fibrinogen on postoperative day 1 can only be explained through the enhanced use of important amounts of de novo synthesized fibrinogen, which was on average 2 g/day for hepatectomies, and 6 g/day for pancreatectomies. Taking into consideration the fibrinogen half-time, which in normal conditions is around 4 days (27), this additional output of fibrinogen should have been noticed on plasma concentrations unless a fast utilization occurred. The fibrinogen exit from the plasma pool is commonly associated with fibrin formation. The utilization of fibrinogen in the coagulation process is increased intraoperatively compared to normal conditions (28). In our study TAT levels on postoperative day 1 indicated a certain coagulation activation and implicitly an increased fibrinogen utilization, to the same extent in liver and pancreas surgery. However, the levels of soluble fibrin monomers showed that the ongoing cleavage of fibrinogen by thrombin, which is exacerbated intra-operatively (29, 30), decreased hastily after pancreatectomies, while following major liver surgery the process was slower. Although the magnitude of the active fibrin formation is hard to be estimated, as indicated by fpB levels, this seems not to be high on postoperative day 1 and onwards. There is evidence that even under trauma or surgical operations fibrin formation might not be the main utilization pathway for fibrinogen (28). Hence, alternative utilization may contribute to the plasma fibrinogen levels. Unfortunately, although intuited, these pathways are not described until now (31, 32). An increased trans-capillary escape might also be involved.
Plasma fibrinogen is essential for balanced coagulation. ROTEM mostly showed balanced coagulation following both types of surgery, which for liver surgery is in agreement with previous studies (12, 26). However, following pancreatectomies, increased plasma fibrinogen concentrations on postoperative days 3–5 affected the ROTEM firmness parameter MCF towards the hypercoagulability area. The portal vein thrombosis observed in one of the patients with signs of hypercoagulability in three ROTEM parameters might be a consequence of a pro-thrombotic state generated by high plasma fibrinogen concentration.
For albumin there is a well-characterized redistribution starting already during the surgical procedure, resulting in a sharp decrease in plasma concentrations (14, 15). There are no major losses of albumin by degradation or loss out of the body to explain the decrease in concentration, so the initial step is redistribution to the extravascular space. De novo synthesis rates are unaffected or increased. In the hepatectomy group, the synthesis rate for albumin was unchanged under the entire explored period. By all means, taking into consideration the massive loss of liver tissue following hemihepatectomies, there was indeed an increase in albumin synthesis per tissue unit in the remnant liver. In this study on postoperative day 1 there was an increase of albumin synthesis rates in the pancreatectomy group, compared to earlier studies when they are found unaltered on postoperative day 2 (15). The increase of the novo synthesis of albumin, following pancreatectomies on postoperative day 1 over the preoperative baseline, was in absolute value around 4 g/day; this was insufficient to influence plasma albumin concentrations.
The albumin synthesis is suggested to be regulated primarily by the colloid osmotic pressure (18). Inflammation in general has a stimulatory effect on albumin synthesis as well (33). In our study albumin synthesis was stimulated on postoperative day 1 but not on postoperative days 3–5, which, under the condition of constant low albumin plasma concentrations, favors the inflammation as a stimulatory factor.
It was within our hypothesis that any differences in plasma concentrations of fibrinogen between the two groups of surgical patients studied may be attributable to a difference in liver mass resulting from the surgical procedure. However, there were also some other differences between the two groups regarding fibrinogen utilization, so it is not possible to conclude anything to be attributable to the difference in liver mass. Still, we intended to have a comparable surgical trauma in the upper abdomen to see what was related to the surgical procedure per se and the reduction in liver mass.
Our findings in this descriptive observational study gain their full meaning when related to their clinical contexts. A predictable postoperative rate of increase in plasma fibrinogen may affect the decision on fibrinogen supplementation. Studies performed in cardiac surgery or cystectomy with massive bleeding show that during the first 24 postoperative hours the plasma fibrinogen concentrations increase at a predictable rate if fibrinogen is not supplemented (34, 35). On postoperative day 1, they reach the same values as preoperative, regardless of the administration or not of fibrinogen concentrate (34–36), suggesting that the administration of fibrinogen in excess is disposed by the organism, or slows the synthesis. We showed that the liver synthesis of fibrinogen following major abdominal surgery is modulated postoperatively to eventually reach the levels of plasma fibrinogen to which the organism is accustomed, which are the preoperative ones. This makes the postoperative plasma fibrinogen concentrations predictable even following hemihepatectomies with no risk for post-hepatectomy liver failure related to low fibrinogen availability. Concerning albumin, in our patients following hepatectomies the tendency of albumin synthesis to increase towards postoperative days 3–5, when inflammation stimuli were, by all means, negligible, suggested a good synthetic function of the regenerating liver. Studies demonstrate that the regeneration of the liver tissue volume is considerable during the first week after liver resections (37), but there were no reports until now regarding the in-vivo synthetic functionality of the new liver tissue in humans. The role of fibrinogen in liver regeneration following hepatectomies is discussed increasingly (38) and our study of fibrinogen synthesis in the remnant liver holds significance even in this area of research.
The strengths of our study are the techniques to assess the synthesis rate of liver export proteins quantitatively and to put these in relation to functional parameters related to plasma concentrations and to liver function in connection with surgical trauma. There are also some limitations to our study, including the relatively small number of subjects available, which meant that describing the synthesis trends for patients following extended hemihepatectomies was unattainable. Another notable limitation was the lack of techniques to quantitatively assess the disappearance rates for fibrinogen and albumin in vivo.
In this study we were able to report patterns for fibrinogen and albumin in terms of plasma concentrations and de novo synthesis perioperatively in conjunction with larger upper abdominal surgery with and without reduction of liver mass. For fibrinogen, there was a dramatic increase in de novo synthesis rate on postoperative day 1, although plasma concentrations were decreased following liver resections or unaltered following pancreatic resections. Also, on postoperative days 3–5 the hepatectomy group had a higher de novo synthesis rate of fibrinogen compared to the preoperatively values. By the end, the results of these synthesis modifications were a return to the preoperative plasma fibrinogen concentrations in the hepatectomy group, and an overshoot in plasma concentrations of fibrinogen in the pancreatectomy group with an intact liver mass. Albumin de novo synthesis was maintained or marginally increased in contrast to the dramatically decreased concentrations. So, in spite of an over 50% reduction in liver mass after hemihepatectomy the characteristic response in changes in concentrations and de novo synthesis of fibrinogen and albumin perioperatively remained grossly similar after a major reduction in liver mass as compared to surgery of comparative size. However, the alterations were less pronounced after hepatectomy compared to pancreatectomy, possibly related to the reduced liver mass.