Patients with obstructive jaundice have abnormal coagulation mechanisms, which manifest as elevated fibrinogen and platelet activation in the early stages and decreased coagulation function in the later stages as liver function damage increases. Surgical and other yellowness-reducing modalities allow bile drainage to be unobstructed, and the patient’s coagulation function is altered to promote recovery of liver function and normal physiological function of multiple organs throughout the body. In this paper, we retrospectively analyzed the clinical data of 63 patients with obstructive jaundice in our hepatobiliary and pancreatic wards to explore the changes of coagulation function in the perioperative period after pancreaticoduodenectomy in patients with obstructive jaundice and the impact on postoperative complications to guide treatment. Wang Xinbo, Department of General Surgery, General Hospital of Nanjing Military Region.
1, Data and methods
1.1, General data: a total of 63 patients with obstructive jaundice who underwent pancreaticoduodenectomy in our hepatobiliary and pancreatic wards from February 2011 to August 2012 were collected, excluding patients with congenital coagulation dysfunction, a history of chronic liver disease and those who took anticoagulant drugs for a longer period of time before the onset, and finally 63 patients were included in the observation, including 41 males and 22 females; age 35-78 years, mean 58.7± 9.8 years old. The postoperative pathology confirmed 31 cases of pancreatic head cancer, 8 cases of pot-belly cancer, 9 cases of lower bile duct cancer, 12 cases of duodenal papillary cancer, and 3 cases of others. The patients were divided into 3 groups according to the serum bilirubin level within 72 h before surgery: those without jaundice were group A (n=19); those with total bilirubin (TIBL) <171 umol/L in jaundiced patients were group B; those with TIBL ≥171 umol/L were group C.
1.2. Surgical methods: 63 patients underwent conventional pancreaticoduodenectomy (child reconstruction), and pancreatic-intestinal anastomosis was performed according to the texture of the pancreatic stump, the thickness of the pancreatic duct and the operator’s experience, including mucosa-to-mucosa anastomosis of the pancreatic duct jejunum, placing a support tube inside the pancreatic duct to drain out of the body in 59 cases, and sleeve-type end-lateral pancreatic-intestinal anastomosis in 4 cases; a T-tube was placed inside the biliary-intestinal anastomosis to support drainage to drain out of the body. Double trocar drains were routinely placed at the bile-intestinal anastomosis. At the same time, jejunostomy was performed intraoperatively to facilitate the implementation of early postoperative enteral nutrition.
1.3. Specimen collection and index testing: All patients were enrolled to collect blood from the elbow vein in the early morning on an empty stomach 1 d before surgery, 7 d and 14 d after surgery to determine routine coagulation indexes and thromboelastography (TEG), and the blood was sent for testing immediately after drawing to exclude interfering factors. Coagulation tests were performed using the CA-7000 fully automated thrombosis/hemostasis analyzer from SYSMEX, Japan, including prothrombin time (PT), partial activation thromboplastin time (APTT), international normalized ratio (INR) and fibrinogen (FIB); platelets (Plt) were measured using the SYSMEX HST302 blood pipeline from SYSMEX, Japan. TEG was measured by Haemoscope 5000 series thromboelastograph and kaolin accelerator provided by Haemoscope, and the measurement indexes were: R value (reaction time) normal range 5-10 min, reflecting the role of coagulation factors, the higher the R value the lower the activity of coagulation factors. k value (clot formation time) was the time used from the end of R value to the amplitude of 20 mm K value (clot formation time) is the time taken from the end of R value to the amplitude of 20mm, normal range 1-3min; Angle value (blood formation rate) is the angle between the tangent line and the horizontal line from the point of clot formation to the maximum arc of the tracing chart, normal range 53-72; K value and Angle value reflect the level of fibrinogen and the function of some platelets; MA value (maximum reaction amplitude) reflects the maximum strength of the clot, mainly depends on the quality and quantity of platelets, normal range 50-70mm. range 50-70mm.
1.4, Statistical analysis: SPSS18.0 was applied.
Statistical software was used to analyze the data, and the measurement data were expressed as mean ± standard deviation (±s) or median (5%-95% quantile) according to whether they conformed to normal distribution, respectively; two-sample t-test was used to compare the means of two groups; one-way ANOVA was used to compare the dynamic changes of means within groups, and LSD method was used for two comparisons; x2 test was used for comparison of rates. The difference was considered statistically significant at P < 0.05.
2, Results
2.1. General perioperative data of 63 patients undergoing pancreaticoduodenectomy.
Sixty-three patients with pancreaticoduodenectomy (Child reconstruction) were divided into 19 patients without jaundice, 28 with moderate jaundice, and 16 with severe jaundice. The general data of age, gender, total bilirubin, days of jaundice, tumor source, bile duct diameter, pancreatic duct diameter, pancreatic-intestinal anastomosis, intraoperative blood transfusion, operation time, intraoperative blood loss, and hospitalization time in each group are shown in Table 1. the more severe jaundice, the differences in bile duct diameter, intraoperative bleeding, and postoperative hospitalization time were statistically significant between the groups (P < 0.05).
2.2 Each index of routine coagulation and TEG in 63 patients.
FIB was increased in jaundiced patients with pancreaticoduodenectomy compared with those without jaundice, and the difference in FIB at 7 d postoperatively was statistically significant (P < 0.05), while the remaining differences in APTT, PT, INR and Plt were not statistically significant. As for the pre- and post-operative comparison of the jaundiced patients themselves, only the difference in PT values at 14 d postoperatively was statistically significant (P < 0.05), while the rest of the differences were not statistically significant. See Table 2. However, the comparison of perioperative TEG indices between 63 jaundiced and nonjaundiced patients detected by thromboelastography was significantly different. There was a gradual decrease in R and K values and a gradual increase in Angle and MA values in the jaundiced group, and there was a statistically significant difference in the perioperative R, K, Angle, and MA values in jaundiced patients compared with those in patients without jaundice (P < 0.05). For the comparison of jaundiced patients before and after their own surgery, there was a statistically significant difference in R, K, and Angle values at 7 d after surgery compared with those before surgery (P < 0.05); and there was a statistically significant difference in R, Angle, and MA values at 14 d after surgery compared with those before surgery (P < 0.05). It suggests that the perioperative coagulation function of patients after pancreaticoduodenectomy has improved.
2.3, The effect of preoperative jaundice degree on postoperative complications after pancreaticoduodenectomy.
According to the preoperative serum total bilirubin level, 63 patients were divided into groups A, B and C. Postoperative complications occurred in 28 cases among 63 patients, with a complication rate of 44.4% and 2 cases of death, both of which were gastrointestinal anastomotic bleeding, with a mortality rate of 3.2%. There was a statistically significant difference in the incidence of postoperative gastrointestinal bleeding in group C compared with group A (x2=3.86, P=0.048), and the incidence of postoperative bleeding also tended to increase gradually with the increase of bilirubin level. The remaining preoperative bilirubin levels had no significant effect on postoperative death, reoperation, abdominal bleeding, pancreatic fistula, biliary fistula, impaired gastric emptying, abdominal infection, incisional infection and pulmonary infection.
3. Discussion
Patients with obstructive jaundice have significant preoperative coagulation dysfunction, and thromboelastography (TEG) tests suggest that the plasma hypercoagulable state may depend on high fibrinogen levels, while platelet counts are also involved.Cakiret al’s study found that the hypercoagulable state in patients with obstructive jaundice was associated with platelet hyperfunction, and Wang Xinbo et al. similarly concluded that patients with obstructive jaundice have a platelet hyperfunction The possible causes of hypercoagulability are: the biliary system is in a state of high pressure and prolonged biliary stasis causes damage to liver function or insufficiency, resulting in a limited ability of the liver to produce coagulation factors; the lack of bile in the intestinal cavity affects the absorption of fat-soluble vitamin K; endotoxemia associated with obstructive jaundice damages vascular endothelial cells, causing tissue factor expression and activation of the exogenous coagulation system, and endotoxin also Endotoxin can also activate the endogenous coagulation system by directly activating the coagulation factor Ⅻ, and the microvascular damage caused by endotoxin increases vascular permeability, causes plasma loss from the circulation resulting in hypercoagulation, increased blood viscosity, and decreased blood flow rate.
Surgical drainage of bile can significantly reduce the serum total bilirubin level, but surgical trauma, etc., is also an important factor causing postoperative coagulation disorders. Since routine coagulation monitoring only reflects one point or part of the time course of the coagulation or fibrinolytic process, it does not truly reflect the balance of effusion and coagulation in the body. Thromboelastography (TEG) can detect the whole process of coagulation and fibrinolysis, i.e., clot formation, determine the rate and intensity of clot generation and clot stability, and can dynamically assess the effect of platelet-coagulation cascade reaction interaction on plasma factor activity. teg is more likely to detect the hypercoagulable state of blood (decreased R value, increased Angle, MA value) than PT and APTT, and teg is more effective than plasma-based Plasma-based conventional assays are more sensitive to monitor fibrinolytic status. Although many factors influence postoperative complications after pancreaticoduodenectomy, preoperative hyperbilirubinemia can be considered an independent factor in patients with elevated postoperative complications. In this study, we examined the changes in perioperative coagulation function and the relationship between the degree of preoperative jaundice and complications in patients after pancreaticoduodenectomy by testing routine coagulation and TEG indexes from the general clinical data of 63 patients.
In 63 patients who underwent pancreaticoduodenectomy, routine coagulation and TEG indexes were measured 1d before, 7d and 14d after surgery, from which it can be seen that fibrinogen in routine coagulation indexes was significantly higher in patients with jaundice than in patients without jaundice, indicating that biliary tract obstruction leads to elevated biliary pressure and obstruction of bile excretion by hepatocytes, which stimulates hepatocytes to synthesize plasma fibrinogen and plasma fibrinogen. The elevation of fibrinogen aggravated the hypercoagulable state of the patient. As the bile drains with the surgical reduction of yellowness, fibrinogen tends to decrease gradually, indicating that liver function gradually returns to normal. The thromboelastogram (TEG) more clearly revealed the changes in coagulation function of the patient during the perioperative period. As can be seen from Table 3, the postoperative R values showed a gradual decreasing trend and Angle and MA values showed an increasing trend, indicating that the preoperative patient’s low coagulation factor state due to liver dysfunction gradually improved due to the gradual reduction of jaundice, which may be related to the restoration of the bile-intestinal circulation of bile salts and the increased synthesis of coagulation factors dependent on vitamin K; while the postoperative increase in fibrinogen and platelet count caused the patient to remain in hypercoagulable state. Although the increase in fibrinogen has implications for hypercoagulation, platelet function plays a major role, in agreement with Mahla E et al. The surgical reduction of serum bilirubin levels resulted in statistically significant differences in R-value, K-value, Angle-value, and MA-value compared to preoperative values. Also, we found a gradual increase in the quality and quantity of platelets after surgery, which may be related to platelet activation and aggregation, which is consistent with the study of Maldonadoet al. A group of studies by Kloek et al concluded that the hypercoagulable state present in patients with obstructive jaundice could be completely reversed by bile drainage in jaundiced patients with coagulation and fibrinolytic function, and similar results were found in this paper. By detecting elevated platelet granule membrane glycoprotein-140 (GMP-140) after surgery in patients with obstructive jaundice, Li Li et al. pointed out that surgical trauma can cause platelet activation in vivo, leading to vascular endothelial cell injury associated with postoperative hypercoagulation. Of course, the trauma of surgery and the relative prolonged bed rest of the patient also cause platelet activation and aggregation. Through TEG monitoring, we can detect the coagulation status of postoperative patients in real time and carry out line specific treatment to avoid unnecessary thrombotic events or blind transfusion of blood products.
By can be seen that there is a significant correlation between the increasing degree of jaundice and intraoperative bleeding, postoperative bleeding and postoperative hospital stay, while there is no significant effect on other complications. A recent analysis of 935 patients with different degrees of jaundice included by Feng Jian et al found that the incidence of bleeding tended to increase with increasing bilirubin levels. postoperative bleeding occurred in 5 of 63 patients, 2 in the moderate jaundice group and 3 in the severe jaundice group, and all of them had gastrointestinal bleeding. although the sample size was small, it can be seen from this that the risk of postoperative bleeding increases with increasing jaundice. Rumstadt et al noted that preoperative biliary drainage did not affect the occurrence of postoperative bleeding and its type and mortality in patients with jaundice, but the rate of gastrointestinal bleeding was significantly higher in patients with jaundice than in those without jaundice. The two deaths from gastrointestinal anastomosis bleeding may be due to decreased gastric mucosal function in patients with obstructive jaundice. Cao Li et al. reported that the risk of bleeding was significantly higher in patients with preoperative total bilirubin above 171 umol/L than in patients with less than 171 umol/L.
With advances in basic and clinical research such as molecular biology and genomics, it has been found that tumors are no longer a single localized disease, but a localized response to a systemic disease, the result of an overall imbalance in the balance of the organism as a biological system. Then, although the local lesion causing obstructive jaundice is surgically removed, the tumor cells are already present in the systemic blood, and the release of ADP from the tumor cells activates platelets to cause them to aggregate. Tumor cells interact with platelets, coagulation factors and fibrin with their procoagulant products such as tissue factor (TF), cancer procoagulant (CP) tumor mucin and coagulation factor V receptor, which contribute to hypercoagulation formation, in addition to cytokine release, acute phase response and other host responses resulting from interactions between tumor cells and endothelial cells, tumor-associated macrophages, which further promote activation of the coagulation pathway . Although prolonged anesthesia, intraoperative blood loss and fluid transfusion, intraoperative and postoperative hypothermia, acidosis or hypocalcemia can all contribute to the effects of prothrombin and coagulation factors on the coagulation function of the body in patients, this study only preliminarily investigated the changes in coagulation function in patients after surgery by reducing serum bilirubin levels by means of one-factor surgical drainage. In conclusion, patients with obstructive jaundice have a preoperative hypercoagulable state dominated by reduced coagulation factors and platelet hyperactivation, and a hypercoagulable state dominated by increased fibrinogen and platelet hyperactivation due to the effects of anesthesia, surgical trauma, intraoperative blood loss, reduced bilirubin levels, etc. As for the specific mechanism of perioperative coagulation changes in patients after pancreaticoduodenectomy and the specific role of each influencing factor on its effect need further in-depth study. Therefore, we only closely observe and prevent thrombosis after surgery in patients with obstructive jaundice from a clinical point of view, and at the same time prevent the occurrence of postoperative bleeding complications through the detection of TEG, early detection, timely treatment, and preventive medication.