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Liver regeneration and platelets
Abstract
The presence of platelets is crucial
... Nevertheless, few papers have studied pre-surgical clinical and biochemical factors that may influence liver regeneration rate. Some studies show that pre-surgical factors such as age, gender, body mass index (BMI), native liver disease, chemotherapy, platelet count, and steatosis might influence liver regeneration (2,(14)(15)(16)(17). The aims of this study were to compare liver regeneration after liver resection in living donors for LRLT and patients with malignancies within a single institution and determine if pre-surgical factors such as age, weight, height, BMI, original liver volume, FRL, spleen volume, liver function tests, creatinine, platelet count, steatosis, portal vein embolization (PVE), and number of segments resected have a significant predictive value for liver regeneration. ...
... The human liver is able to regenerate due to a hyperplastic reaction in the residual liver (1). Some studies suggest that presurgical factors such as age, gender, BMI, native liver disease, chemotherapy, platelet count, and steatosis might have a significant influence on human liver regeneration (2,(14)(15)(16)(17). One study in particular demonstrates that an elevated platelet counts in mice after 90% hepatectomy is beneficial for liver regeneration (21). ...
The purpose of the study is to detect if some parameters can be considered as predictors of liver regeneration in two different patient populations composed of in living donors for adult to adult living donor liver transplant and patients with hepatic malignancies within a single institution.
Preoperative multi-detector computed tomography volumetry is an essential tool to assess the volume of the remnant liver.
A retrospective analysis from an ongoing clinical study on 100 liver resections, between 2004 and 2010. Seventy patients were right lobe living donors for liver transplantation and 30 patients were resected for treatment of tumors. Pre-surgical factors such as age, weight, height, body mass index (BMI), original liver volume, future remnant liver volume (FRLV), spleen volume, liver function tests, creatinine, platelet count, steatosis, portal vein embolization, and number of resected segments were analyzed to evidence potential markers for liver regeneration.
Follow-up period did not influence the amount of liver regenerated: the linear regression evidenced that there is no correlation between percentage of liver regeneration and time of follow-up (p = 0.88). The pre-surgical variables that resulted markers of liver regeneration include higher preoperative values of BMI (p = 0.01), bilirubin (p = 0.04), glucose (p = 0.05), and gamma-glutamyl transpeptidase (p = 0.014); the most important association was revealed regarding the lower FRLV (p < 0.0001) and percentage of liver regeneration. The stepwise regression revealed a strong impact of FRLV (p < 0.0001) on the other predictor variables.
Liver regeneration follows similar pathway in living donor and in patients resected for cancer. Small FRLV tends to regenerate more and faster, confirming that a larger resections may lead to a greater promotion of liver regeneration in patients with optimal conditions in terms of body habitus, preoperative liver function tests, and glucose level.
... 7,8 Some studies have analyzed presurgical clinical and biochemical factors that may influence the rate of liver regeneration, and they have posited that presurgical factors such as age, sex, body mass index (BMI), native liver disease, chemotherapy, platelet counts, and steatosis may influence regeneration. 6,[9][10][11][12] The aims of this study were to study FRLV regeneration in living donors 60 days after right hepatectomy for living related liver transplantation and to determine which preoperative clinical variables (if any) have a significant predictive value for early regeneration. ...
... 5 Some studies have suggested that presurgical variables such as age, sex, BMI, native liver disease, chemotherapy, platelet counts, and steatosis may have a significant influence on human liver regeneration. 6,[9][10][11][12]22 One study in mice found that elevated platelet counts after 90% hepatectomy were beneficial for liver regeneration, 23 whereas another study in humans concluded that thrombocytopenia could follow right hepatectomy for living donation. 5 Given the available data, we wanted to determine which presurgical factors (if any) are potential early markers of liver regeneration in right lobe living donors for living related liver transplantation. ...
Early liver regeneration was studied in a series of 70 patients who underwent right hepatectomy for living donation between November 2004 and January 2010. Liver regeneration was evaluated with multidetector computed tomography (MDCT) at a mean of 61.07 days after surgery. Presurgical variables [eg, age, weight, height, body mass index (BMI), liver function tests, creatinine levels, platelet counts, international normalized ratio, and glucose levels] and variables detected with preoperative MDCT imaging [eg, main portal vein diameter, steatosis, original liver volume, and spleen volume (SV)] were investigated as potential predictors of liver regeneration. The future remnant liver volume (FRLV) was preoperatively calculated with a virtual surgical cut. Liver function tests and creatinine levels were recorded on the 30th postoperative day. In addition, the onset of postoperative complications occurring within 90 days of surgery was analyzed, and the complications were codified according to the 5 tiers of the Clavien-Dindo classification. In 26 of the 70 patients (37.14%), 100% or greater hepatic regeneration had occurred at 2 months. There was no association between the clinical outcome and the liver regeneration rate. A stepwise multiple regression analysis showed that a higher BMI (coefficient = 0.035, P < 0.0001) and preoperative parameters such as a smaller FRLV (coefficient = -0.002, P < 0.0001) and a greater SV/FRLV ratio (coefficient = 1.196, P < 0.0001) were predictors of greater liver regeneration.
... Qaraciyərin regenerasiyası üçün transplantasiyadan sonra keçən vaxt əhəmiyyətli sayılır. Eyni zamanda, xəstənin yaşı, cinsi, BKİ kimi demoqrafik göstərilər, trombosit sayı, steatoz dərəcəsi kimi kliniki və biokimyəvi faktorların regenerasiya qabiliyyətinə təsir etdiyi söylənilməkdədir [10,11,12]. ...
Donor safety is very importance in Living donor liver transplantation (LDLT). However, most recent reports have focused on analyses of postprocedural recipients morbidity, while complications in donors have not been fully investigated. The literature analysis showed that delayed liver function recovery and morbidity were significantly correlated with the functional liver mass. Presurgical body mass index (BMI), liver function tests, platelet counts, international normalized ratio, steatosis, and spleen volume were investigated as potential predictors of liver regeneration. Also, there is no association between the liver regeneration rate and the clinical outcome. Donor safety will be evaluated by the graft type, frequency, and severity of postoperative complications the using of the Clavien-Dindo classification system.
... However, firstly the hemodynamic situation of recovering animals would certainly be stabilized and secondly the decrease of PBF, when liver restoration occurred, has already been described as a comparatively slow process in contrast to the rapid decline in the end stage of ALF [28] . It has recently been demonstrated experimentally [27,34] and clinically [35,36] that thrombocytes are able to promote liver regeneration after extended hepatectomy or liver transplantation. Their predictive value in the context of ALF remains unclear. ...
AIM
To investigate the changes of hemodynamic and laboratory parameters during the course of acute liver failure following acetaminophen overdose.
METHODS
Eight pigs underwent a midline laparotomy following jejunal catheter placement for further acetaminophen intoxication and positioning of a portal vein Doppler flow-probe. Acute liver failure was realized by intrajejunal acetaminophen administration in six animals, two animals were sham operated. All animals were invasively monitored and received standardized intensive care support throughout the study. Portal blood flow, hemodynamic and ventilation parameters were continuously recorded. Laboratory parameters were analysed every eight hours. Liver biopsies were sampled every 24 h following intoxication and upon autopsy.
RESULTS
Acute liver failure (ALF) occurred after 28 ± 5 h resulted in multiple organ failure and death despite maximal support after further 21 ± 1 h (study end). Portal blood flow (baseline 1100 ± 156 mL/min) increased to a maximum flow of 1873 ± 175 mL/min at manifestation of ALF, which was significantly elevated (P < 0.01). Immediately after peaking, portal flow declined rapidly to 283 ± 135 mL/min at study end. Thrombocyte values (baseline 307 × 10³/µL ± 34 × 10³/µL) of intoxicated animals declined slowly to values of 145 × 10³/µL ± 46 × 10³/µL when liver failure occurred. Subsequent appearance of severe thrombocytopenia in liver failure resulted in values of 11 × 10³/µL ± 3 × 10³/µL preceding fatality within few hours which was significant (P > 0.01).
CONCLUSION
Declining portal blood flow and subsequent severe thrombocytopenia after acetaminophen intoxication precede fatality in a porcine acute liver failure model.
... Some studies have suggested that preoperative variables such as age, gender, BMI, native liver disease, chemotherapy, platelet count and steatosis may have a significant influence on human liver regeneration [2,[24][25][26][27] . With this in mind we wanted to investigate whether postoperative infective complications would have any impact of early liver regeneration in patients resected for hepatic tumors on otherwise healthy livers. ...
Aim:
To investigate whether early liver regeneration after resection in patients with hepatic tumors might be influenced by post-operative infective complications.
Methods:
A retrospective analysis of 27 liver resections for tumors performed in a single referral center from November 2004 to January 2010. Regeneration was evaluated by multidetector computed tomography at a mean follow-up of 43.85 d. The Clavien-Dindo classification was used to evaluate postoperative events in the first 6 mo after transplantation, and Centers for Disease Control and Prevention definitions were used for healthcare associated infections data. Generalized linear regression models with Gaussian family distribution and log link function were used to reveal the principal promoters of early liver regeneration.
Results:
Ten of the 27 patients (37%) underwent chemotherapy prior to surgery, with a statistically significant prevalence of patients with metastasis (P = 0.007). Eight patients (30%) underwent embolization, 3 with primary tumors, and 5 with secondary tumors. Twenty patients (74%) experienced complications, with 12 (60%) experiencing Clavien-Dindo Grade 3a to 5 complications. Regeneration ≥ 100% occurred in 10 (37%) patients. The predictors were smaller future remnant liver volume (-0.002; P < 0.001), and a greater spleen volume/future remnant liver volume ratio (0.499; P = 0.01). Patients with a resection of ≥ 5 Couinaud segments experienced greater early regeneration (P = 0.04). Nine patients experienced surgical site infections, and in 7 cases Clavien-Dindo Grade 3a to 4 complications were detected (P = 0.016). There were no significant differences between patients with primary or secondary tumors, and either onset or infections or severity of surgical complications.
Conclusion:
Regardless of the onset of infective complications, future remnant liver and spleen volumes may be reliable predictors of early liver regeneration after hepatic resection on an otherwise healthy liver.
... It is well known that platelets play an important role in wound healing and tissue regeneration (16). Platelets contain proteins needed for haemostasis and growth factors including platelet-derived growth factor (PDGF), hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), tumour growth factor (TGF) and serotonin (5HT), required for tissue regeneration (17)(18)(19)(20)(21)(22). Recently, it has been reported that platelets prevent hepatic failure and stimulate liver regeneration after extensive hepatectomy by releasing growth factors (23)(24)(25)(26)(27)(28). ...
Ninety per cent hepatectomy in rodents is a model for acute liver failure. It has been reported that platelets have a strong effect enhancing liver regeneration, because of the production of several growth factors such as serotonin. The aim of this study was to investigate the role of microencapsulated platelets on 90% hepatectomy in rats.
Platelets (PLT) were microencapsulated in sodium alginate and implanted in the peritoneum of rats after 90% partial hepatectomy (PH). Control group received empty capsules (EC). Animals were euthanized at 6, 12, 24, 48 and 72 h post PH (n = 9-12/group/time) to evaluate liver regeneration rate, mitotic index, liver content, serum and tissue levels of Interleukin 6 (IL-6) and serotonin and its receptor 5-hydroxytryptamine type 2B (5Ht2b). Survival rate in 10 days was evaluated in a different set of animals (n = 20/group).
Platelets group showed the highest survival rate despite the lowest liver regeneration rate at any time point. Mitotic and BrdU index showed no difference between groups. However, the number of hepatocytes was higher and the internuclear distance was shorter for PLT group. Liver dry weight was similar in both groups indicating that water was the main responsible factor for the weight difference. Gene expression of IL-6 in the liver was significantly higher in EC group 6 h after PH, whereas 5Ht2b was up-regulated at 72 h in PLT group.
Platelets enhance survival of animals with 90% PH, probably by an early protective effect on hepatocytes and the increase in growth factor receptors.
Background
Little is known about the clinical significance and risk factors for incomplete liver restoration after partial hepatectomy, which is defined by a liver volume restoration of less than 100% of the original volume.
Methods
We retrospectively analyzed patients who underwent hepatic resection for liver tumors at the Kyoto University Hospital between January 2011 and October 2015 and survived without recurrence for more than 3 years. The preoperative and postoperative data, as well as liver and splenic volume after 3 postoperative years, were assessed.
Results
The percentage of resected liver was higher in the incomplete liver restoration group (n = 52, 41.6%) than in the complete liver restoration group (n = 73, 58.4%) (28 [3–78]% vs 14.5 [2–63]%, P = .0226). The percentage of resected liver was also higher in the splenomegaly group (defined by spleen volume increases of more than 35% of the original volume) than in the nonsplenomegaly group (40 [4–63]% vs 16.5 [2–78]%, P = .0002). Multivariate analysis demonstrated that the percentage of resected liver was a significant predictor of incomplete liver restoration (odds ratio = 9.75, P = .0043) and splenomegaly (odds ratio = 74.4, P = .0006). Incomplete liver restoration 3 years after hepatectomy was associated with lower serum albumin levels (4.0 [2.4–4.7] g/dL compared with 4.2 [2.6–4.8] g/dL in the complete liver restoration group, P = .0032). Splenomegaly was associated with a lower platelet count (109.9 ± 49.8 x10³/μL vs 163 ± 58.1 × 10³/μL,P = .0007) and lower serum albumin level (3.6 [2.6–4.4] g/dL vs 4.1 [2.4–4.8] g/dL, P = .0002).
Conclusion
An extensive resection of the liver parenchyma results in an increased risk for incomplete liver restoration and splenomegaly long after hepatectomy, which is associated with the clinical consequences of hypoalbuminemia and thrombocytopenia.
Background:
Clinical and biological factors that predict liver volume recovery rate (LVRR) after liver resection of different resected volume (RV) have not been studied extensively. Moreover, it remains uncertain whether remnant liver volume influences the liver function recovery rate (LFRR). This study examined the predictive factors for LVRR after liver resections of different RV and investigated LFRR by focusing on LVRR improvements after hepatectomy.
Methods:
Patients who underwent hepatectomy between January 2013 and August 2015 were reviewed retrospectively. LVRR and LFRR were assessed at postoperative months (POMs) 3, 6, and 12. LVRR was evaluated on the basis of RV (0%-15%, 15%-30%, 30%-45%, and >45%). LFRR was evaluated using total bilirubin, prothrombin time, and platelet count.
Results:
LVRR was lower with more extensive liver resections. Significant independent predictors of LVRR were type IV collagen 7s domain levels and resection magnitude. Platelet count correlated positively with LVRR at all POMs.
Conclusions:
Resected livers regenerated after surgery but did not reach preoperative volumes. Preserving the liver as much as possible during resection can result in greater LFRR after hepatectomy. Therefore, decisions regarding liver resection volume should be made very carefully, particularly in patients with higher type IV collagen 7s domain levels.
Portal vein embolization (PVE) has been developed to increase the size of the future remnant liver (FRL) left in place after major hepatectomy, thus reducing the risk of postoperative liver insufficiency. PVE consist in embolizing preoperatively portal branches of the segments that will be resected. Indication is based on preoperative measurements of the FRL by computed tomography and its ratio with either the theoretical liver volume or by direct measurement of the functional liver volume. After PVE, the volume and function of the FRL increases in 3 to 6 weeks, permitting extensive resections in patients otherwise contraindicated for liver resection. The PVE technique is variable from one center to another; however n-butyl-cyano-acrylate provides an interesting compromise between hypertrophy rate and procedure risk.
In the past two decades, hepatic surgery has achieved important technical breakthroughs resulting in a drastic reduction of the onset of complications and in an improved post-resective survival. Pre-operative nutritional status is one of the key points for the success of a liver resection. Modern surgical achievement such as the development of living-related liver donation, and the possibility to perform more laparoscopic liver resection gave us the opportunity to extend post-operative protocol focused on early intestinal feeding to tumor patients. The aims of this review were to report the current status of the knowledge regarding nutritional aspects in liver resection patients.
The liver carries out a range of functions essential for bodily homeostasis. The impairment of liver functions has serious implications and is responsible for high rates of patient morbidity and mortality. Presently, liver transplantation remains the only effective treatment, but donor availability is a major limitation. Therefore, artificial and bioartificial liver devices have been developed to bridge patients to liver transplantation. Existing support devices improve hepatic encephalopathy to a certain extent; however their usage is associated with side effects. The major hindrance in the development of bioartificial liver devices and cellular therapies is the limited availability of human hepatocytes. Moreover, primary hepatocytes are difficult to maintain and lose hepatic identity and function over time even with sophisticated tissue culture media. To overcome this limitation, renewable cell sources are being explored. Human embryonic stem cells are one such cellular resource and have been shown to generate a reliable and reproducible supply of human hepatic endoderm. Therefore, the use of human embryonic stem cell-derived hepatic endoderm in combination with tissue engineering has the potential to pave the way for the development of novel bioartificial liver devices and predictive drug toxicity assays.
Widespread application of cadaveric split or living donor liver transplantation bears considerable potential to increase the pool of available organs and thus alleviate the problem of organ shortage. Although splitting of a cadaveric liver into two grafts for adult recipients can be performed successfully, sufficient function of undersized grafts is a major concern. To minimize the risk for living donors, transplant surgeons aim at procuring the least necessary liver volume, also leading to potentially small grafts. When small partial grafts are unable to meet the functional demands, the recipients can develop a so-called small-for-size syndrome (SFSS). There is currently limited data on the pathogenesis of SFSS, with clinical studies mainly focusing on portal hyperperfusion. Additional aspects include graft-related factors such as functional and regenerative capacity, as well as recipient-related factors, such as overall health status and severity of cirrhosis. However, there is currently no consensus on the definition of SFSS. We propose a novel definition, based on simple clinical criteria, which divides the syndrome into either nonfunction or dysfunction of a small graft after the exclusion of other causes. This definition should ease comparability of future clinical trials, and thus improve understanding of the pathogenesis of SFSS.
The liver can regenerate its volume after major tissue loss. In a mouse model of liver regeneration, thrombocytopenia, or
impaired platelet activity resulted in the failure to initiate cellular proliferation in the liver. Platelets are major carriers
of serotonin in the blood. In thrombocytopenic mice, a serotonin agonist reconstituted liver proliferation. The expression
of 5-HT2A and 2B subtype serotonin receptors in the liver increased after hepatectomy. Antagonists of 5-HT2A and 2B receptors
inhibited liver regeneration. Liver regeneration was also blunted in mice lacking tryptophan hydroxylase 1, which is the rate-limiting
enzyme for the synthesis of peripheral serotonin. This failure of regeneration was rescued by reloading serotonin-free platelets
with a serotonin precursor molecule. These results suggest that platelet-derived serotonin is involved in the initiation of
liver regeneration.
The liver possesses the unique ability to regenerate within a short period of time, a feature that has led to the development of innovative strategies in liver surgery and transplantation. This review presents both established and novel methods for manipulating liver volume to attain improved liver surgery and transplantation.
Sinusoidal endothelial cell (SEC) apoptosis is a central feature of reperfusion injury in liver transplantation. Platelet sequestration occurs after transplantation with possible deleterious effects. We tested the hypothesis that platelets mediate SEC apoptosis.
Livers were perfused after 24 hours of cold preservation in University of Wisconsin solution in an isolated perfused rat liver model. The perfusate contained isolated syngeneic red blood cells and purified platelets. Effects of inhibiting platelet adhesion on SEC apoptosis was tested using sialyl Lewis-X oligosaccharide (sLe(x)), a natural ligand of selectin adhesion molecules. Reperfusion injury was assessed by established markers of injury. Apoptosis was determined by TUNEL and electron microscopy.
A third of the circulating platelets was rapidly sequestered in the liver after reperfusion. This was associated with increased graft injury. Single platelets were adherent to sinusoidal lining without morphological or dynamic evidence of impairment of microcirculation. TUNEL staining revealed a 6-fold increase in the number of apoptotic SECs at 1 hour of reperfusion. No hepatocyte death or evidence of necrosis was detected up to 3 hours of reperfusion. Addition of sLe(x) inhibited adhesion and significantly reduced SEC apoptosis.
Platelets cause SEC apoptosis upon reperfusion of liver grafts. Prevention of adhesion is protective.
Extensive liver resection for hilar bile duct carcinoma with jaundice has high morbidity and mortality rates because of postoperative liver failure. To minimize postoperative liver dysfunction, a portal venous branch was embolized before surgery to induce atrophy of the lobe to be resected and hypertrophy of the contralateral lobe in 14 patients with hilar bile duct carcinoma. Bile was drained before surgery in 11 patients with jaundice. Portal embolization did not produce major side effects, and moderate increases of serum transaminase activity or bilirubin returned to baseline values within 1 week. Hepatectomy with bile duct resection and lymphadenectomy was performed 6 to 41 days after embolization, at which time the embolized lobe was atrophied in 12 of the patients. Extended right or left lobectomy or left trisegmentectomy (10, 3, and 1 cases, respectively) with biliointestinal reconstruction was performed. One patient with jaundice and suppurative cholangitis died 30 days after hepatectomy. Another patient died 3 months after surgery of aggravated hepatitis. After surgery, no bile leakage occurred and hyperbilirubinemia was usually moderate and reversible.
The pathogenesis of alcoholic chronic pancreatitis and its relationship to alcoholic acute pancreatitis are debated. According to our recent clinical long-term study, alcoholic chronic pancreatitis seems to evolve from severe acute pancreatits. The aim of this study was to correlate clinical findings to the pancreatic histopathology at early and advanced stages of the disease.
Morphological changes (pseudocysts, autodigestive necrosis, calcification, and perilobular and intralobular fibrosis) were recorded in 37 surgical and 46 postmortem pancreas specimens of 73 patients from our long-term series, who progressed from clinically acute to chronic pancreatitis (mean follow-up, 12 years). Pancreatic function was monitored at yearly intervals.
Surgical interventions were performed at a mean of 4.1 years from onset. Histologically, focal necrosis (49%) and mild perilobular fibrosis (54%) predominated, Pseudocysts (n = 41, mostly postnecrotic) occurred in 88% within 6 years from onset. Autopsy specimens were obtained at a mean of 12 years. These pancreata often showed severe perilobular and intralobular fibrosis (85%) and calcifications (74%), but rarely necrosis (4%). Fibrosis correlated with progressive pancreatic dysfunction (P < 0.001), particularly in the 10 patients with two histological assessments (mean interval between biopsy and autopsy, 8 years).
The data support an evolution from severe alcoholic acute pancreatitis to chronic pancreatitis.
Liver regeneration after the loss of hepatic tissue is a fundamental parameter of liver response to injury. Recognized as a phenomenon from mythological times, it is now defined as an orchestrated response induced by specific external stimuli and involving sequential changes in gene expression, growth factor production, and morphologic structure. Many growth factors and cytokines, most notably hepatocyte growth factor, epidermal growth factor, transforming growth factor-alpha, interleukin-6, tumor necrosis factor-alpha, insulin, and norepinephrine, appear to play important roles in this process. This review attempts to integrate the findings of the last three decades and looks toward clues as to the nature of the causes that trigger this fascinating organ and cellular response.
The advances that have been made over the last decade in microscopic, biochemical, molecular, and genetic techniques have led to substantial improvement in our understanding of platelet dense granule structure and function, and the implications of dense granule deficiencies for haemostasis. However, much has still to be learned. For example, what is the specific mechanism of docking and fusion that occurs during dense granule exocytosis? What are the roles of dense granule membrane proteins during exocytosis or after expression on the surface of activated platelets? Finally, how do the genetic defects identified in HPS and CHS result in the clinical phenotype of these diseases, and what does this tell us about the origin and function of the affected subcellular organelles?
Liver regeneration after the loss of hepatic tissue is a fundamental parameter of liver response to injury. Recognized as
a phenomenon from mythological times, it is now defined as an orchestrated response induced by specific external stimuli and
involving sequential changes in gene expression, growth factor production, and morphologic structure. Many growth factors
and cytokines, most notably hepatocyte growth factor, epidermal growth factor, transforming growth factor-α, interleukin-6,
tumor necrosis factor-α, insulin, and norepinephrine, appear to play important roles in this process. This review attempts
to integrate the findings of the last three decades and looks toward clues as to the nature of the causes that trigger this
fascinating organ and cellular response.
Hepatic ischemia and reperfusion (I/R) leads to the formation of leukocyte-platelet aggregates. Upon activation, platelets generate reactive oxygen species and release proapoptotic and proinflammatory mediators as well as growth factors. In cold hepatic ischemia, adhesion of platelets to endothelial cells mediates sinusoidal endothelial cell apoptosis. Furthermore, platelet-derived serotonin mediates liver regeneration. We hypothesized that platelets may contribute to reperfusion injury and repair after normothermic hepatic ischemia. The aim of this study was to assess the impact of platelets in normothermic hepatic I/R injury using models of impaired platelet function and immune thrombocytopenia. Inhibition of platelet function in mice was achieved via clopidogrel feeding. Immune thrombocytopenia was induced via intraperitoneal injection of anti-CD41 antibody. Platelet-derived serotonin was investigated using mice lacking tryptophan hydroxylase 1. Mice were subjected to 60 minutes of partial hepatic ischemia and various time points of reperfusion. Hepatic injury was determined via AST and histological analysis of the necrotic area as well as leukocyte infiltration. Liver regeneration was determined via proliferating cell nuclear antigen and Ki67 immunohistochemistry. Neither inhibition of platelet function nor platelet depletion led to a reduction of I/R injury. Liver regeneration and repair were significantly impaired in platelet-depleted animals. Mice lacking peripheral serotonin were deficient in hepatocyte proliferation, but otherwise displayed normal tissue remodeling. Conclusion: Platelets have no direct impact on the pathogenesis of normothermic I/R injury. However, they mediate tissue repair and liver regeneration. Furthermore, platelet-derived serotonin is a mediator of hepatocyte proliferation in the postischemic liver, but has no impact on tissue remodeling.
Mortality after 90% partial hepatectomy in mice was associated with severe acute liver failure. Recently, we revealed that platelets have a strong promotional effect on hepatic regeneration. In the present study, we investigated the effect of thrombocytosis on liver regeneration after 90% hepatectomy in mice.
For thrombocytosis induction PEG-rHuMGDF was injected 5 days before operation. Hepatectomy, sparing only the caudate lobe, was performed in normal and thrombocytotic BALB/c mice. Survival rate, platelet number, liver weight/body weight ratio, proliferating cell nuclear antigen, serum parameters, signal transduction and overexpressed genes were examined.
Platelet number was significantly higher in thrombocytotic group. All mice in normal group died within 30 h after hepatectomy. Survival rate in thrombocytotic group was 6/11 at 30 h and 3/11 one week after hepatectomy. Activation of Akt and STAT3 signaling pathways in thrombocytotic group was observed earlier and recognized to be stronger compared to normal group. Cell cycle, signaling pathways, metabolism and transport genes were significantly overexpressed in thrombocytotic group up to 24h after hepatectomy.
Under the thrombocytotic condition, liver regeneration occurred even in 90% hepatectomized mice. Platelets contribute to cell cycle progression and metabolic pathways in addition to preventing acute liver failure.
Preoperative portal embolization to increase safety of major hepatectomy for hilar bile duct carcinoma: a preliminary report
- Makuuchi