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Clinical influence of preoperative factor XIII activity in patients undergoing pancreatoduodenectomy
HPB
http://dx.doi.org/10.1016/j.hpb.2017.07.002
ORIGINAL ARTICLE
Clinical influence of preoperative factor XIII activity in patients undergoing pancreatoduodenectomy Nobuyuki Watanabe, Yukihiro Yokoyama, Tomoki Ebata, Gen Sugawara, Tsuyoshi Igami, Takashi Mizuno, Junpei Yamaguchi & Masato Nagino Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
Abstract Background: The influence of decreased factor XIII (FXIII) activity on perioperative bleeding has been reported in some surgical procedures. The purposes of this study were to investigate the perioperative dynamics of FXIII in patients undergoing pancreatoduodenectomy and to clarify the effects of low preoperative FXIII activity on intraoperative bleeding and postoperative complications. Methods: Total of 43 patients who underwent a pancreatoduodenectomy were enrolled. The perioperative FXIII activities were measured, and their associations with intraoperative bleeding and postoperative outcomes were analyzed. Results: Fifteen patients (35%) had low FXIII activities (<70%, lower than the institutional normal range). The patients with preoperative FXIII activities <70% experienced significantly greater blood loss (median, 1309 mL) during surgery compared to those with FXIII levels of 70% (median, 710 mL) (p = 0.001). The postoperative morbidity rates, including pancreatic fistula, were comparable between the patients with FXIII activities <70% and those with FXIII activities 70%. The FXIII levels substantially decreased on postoperative day 1 and remained at low levels until postoperative day 7. Conclusion: Unexpectedly high proportions of patients undergoing pancreatoduodenectomy had low preoperative FXIII activities. Preoperative FXIII deficiency may increase intraoperative bleeding but had no influence on the postoperative outcomes. Received 24 March 2017; accepted 2 July 2017
Correspondence Yukihiro Yokoyama, Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan. E-mail: yyoko@med. nagoya-u.ac.jp
Introduction Surgical resection is the only method for curing hepatopancreato-biliary (HPB) malignancies. Although a certain amount of intraoperative blood loss is inevitable in HPB surgery, excessive blood loss may lead to blood transfusions and severe postoperative complications. Indeed, several studies have indicated an association between intraoperative blood loss and postoperative complications.1,2 Additionally, some studies have claimed that perioperative blood transfusions have adverse influences on postoperative morbidity and tumor recurrence.3–7 Factor XIII (FXIII) is a key factor that functions at the end of the coagulation cascade by cross-linking fibrin monomers into stable polymers and counteracting fibrinolytic degradation.8,9 FXIII also This paper has not been presented in any meetings previously.
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plays an important role in wound healing.10 Some studies have reported associations of FXIII activity with perioperative bleeding in cardiac,11,12 gastrointestinal,13 and neurologic surgeries.14,15 However,littleisknownabouttheroleofperioperativeFXIIIactivityinHPB surgeriesparticularly pancreatoduodenectomy. The purpose of the present study was to investigate the perioperative dynamics of FXIII in patients undergoing pancreatoduodenectomy and to clarify whether a preoperative deterioration of FXIII activity was associated with intraoperative blood loss or postoperative complications in these patients.
Methods Patients The study was approved by the ethical review board of the Nagoya University Hospital and was registered with the
© 2017 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Watanabe N, et al., Clinical influence of preoperative factor XIII activity in patients undergoing pancreatoduodenectomy, HPB (2017), http://dx.doi.org/10.1016/j.hpb.2017.07.002
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University Hospital Medical Information Network (registration No. UMIN000014580). Between September 2014 and August 2016, a total of 45 patients who underwent a pancreatoduodenectomy at the Division of Surgical Oncology, Department of Surgery, Nagoya University Hospital, were enrolled. Patients who were administered any anticoagulants before and after surgery were excluded. Written informed consent was obtained from each patient prior to enrollment in the study. Perioperative management Preoperative biliary drainage was performed when obstructive jaundice was confirmed. The externally drained bile was replaced orally or via administration through a nasoduodenal tube.16 The operations were performed when the total serum bilirubin decreased to less than 2 mg/dL. Perioperative antimicrobial prophylaxis was performed immediately before surgery and every 4–12 h (the intervals were determined according to the half-lives of the antimicrobials) during and after surgery (until 2 days after surgery). Cefazolin was generally selected for the patients without external biliary drainage. In patients with preoperative external biliary drainage, the type of antimicrobial was selected according to the results of a drained bile culture.17 The surgeons were blinded to the preoperative FXIII activity results at the time of operation. The replacement of FXIII was not allowed until postoperative day (POD) 7. Surgical techniques In general, we performed subtotal stomach-preserving pancreatoduodenectomies. Pancreatojejunostomy was performed using the duct-to-mucosa anastomosis with modified Blumgart method.18 A pancreatic duct drainage tube was inserted into the main pancreatic duct of the remnant pancreas, and the tube was exteriorized through the end of the blind loop of the jejunum. Blood sampling and data collection Blood samples for analysis were obtained within 1 week before surgery and on PODs 1 and 7. We measured the FXIII activity, prothrombin time % (PT%), activated partial thromboplastin time % (APTT%), fibrinogen level, and complete blood count. All laboratory tests were performed according to the protocol of the manufacturer. FXIII activity was measured via the synthetic substrate method (JCA-EM1650, JEOL Ltd., Tokyo, Japan), with a reference value of 70–140%. APTT% (STA-PTT Automate; Roche) and fibrinogen (STA-Fibrinogen; Roche) were measured using the clotting method. Preoperative low FXIII activity was defined as <70% based on the previous reports.11,14 This cut-off value is also used as lower limit of normal range of FXIII activity in our institution. The data for all participants were prospectively collected. The preoperative characteristics, including the patient’s age, gender, body mass index (BMI), preoperative diagnosis, American Society of Anesthesiologists physical status (ASA PS) classification,
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diabetes mellitus, and main pancreatic duct diameter measured by multiple-detector computed tomography before surgery were recorded. Intraoperative parameters, such as the surgical procedure, operation time, and blood loss, were also recorded. Intraoperative blood loss was calculated by weighing blood soaked gauze and measuring the amount of blood in suction bottles. Postoperative complications that occurred within 28 days after surgery were monitored and classified according to the Clavien–Dindo classification of surgical complications.19 Postoperative pancreatic fistula and delayed gastric emptying were diagnosed and classified based on the definitions of the International Study Group of Pancreatic Surgery.20,21 The incidences of intraoperative and postoperative transfusions were also recorded. Packed red blood cells were usually given when the hemoglobin decreased to <7 g/dl, and fresh frozen plasma was given when the PT%/APTT% value decreased to <40% or bloody fluid was found from the abdominal drains. Statistics The results are expressed as the medians (ranges) for the continuous data. The perioperative dynamics of FXIII activity are illustrated in line graphs with the means and standard deviations. The statistical analyses were performed using the Mann– Whitney U test, dependent t-test, c2 test, or Fisher’s exact probability test as appropriate. A multiple regression analysis was used to identify independent risk factors of intraoperative blood loss. A P value < 0.05 was considered statistically significant.
Results Preoperative FXIII activities and perioperative variables Among total of 45 patients participated in the study, two patients who were intraoperatively diagnosed as having an unresectable tumor were excluded. Therefore, 43 patients were finally analyzed. The preoperative FXIII activities were <70% (less than the institutional normal range) in 15 patients (35%) (Table 1). There were no significant differences between the patients with FXIII activities 70% and <70% in terms of preoperative characteristics. However, the median intraoperative blood loss in the patients with preoperative FXIII activities <70% was significantly greater than that in the patients with preoperative FXIII activities 70% (P = 0.001; Table 2). Additionally, the proportion of patients who received red blood cell or fresh frozen plasma transfusions during surgery was significantly greater among patients with preoperative FXIII activities <70% than among patients with preoperative FXIII activities 70%. The occurrences of clinically significant postoperative pancreatic fistula, delayed gastric emptying, and major postoperative complications with Clavien–Dindo scores IIIa were all comparable between the two groups. A multiple regression analysis of preoperative coagulation parameters revealed that preoperative FXIII activities significantly
© 2017 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Watanabe N, et al., Clinical influence of preoperative factor XIII activity in patients undergoing pancreatoduodenectomy, HPB (2017), http://dx.doi.org/10.1016/j.hpb.2017.07.002
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Table 1 Preoperative characteristics of patients who underwent
Table 2 Intraoperative and postoperative variables in patients who
pancreatoduodenectomy
underwent pancreatoduodenectomy
Preoperative FXIII activity
P value
‡70% (n [ 28)
<70% (n [ 15)
Age [years]
63 (42–86)
71.5 (54–83)
0.149
Male gender
20
11
0.594
BMI [kg/m2]
21.7 (15.2–31.5)
21.2 (18.2–23.7)
0.333
Pancreatic cancer
10
5
IPMN
5
0
Bile duct cancer
9
7
Diagnosis
Ampullary cancer
0.344
4
Preoperative FXIII activity
P value
‡70% (n [ 28)
<70% (n [ 15)
SSPPD
27
15
PD
1
0
Combined PV resection
4
3
0.468
Operation time [min]
460 (270–698)
446 (339–727)
0.809
Blood loss [mL]
710 (204–2296)
1309 (323–4385)
0.001
Procedure
0.651
Intraoperative transfusion
3
ASA PS classification
0.564
Red blood cell
4
9
0.003
Fresh frozen plasma
1
6
0.005
0.349
Class 1
11
4
Class 2
16
10
Class 3
1
1
Diabetes mellitus
9
7
0.348
Biliary drainage
19
13
0.164
Cholangitis
8
7
0.235
Postoperative complications
MPD diameter [mm]
3.5 (1.8–10.2)
4.9 (1.8–19.3)
0.759
POPF (grade B, C)
6
4
0.488
Postoperative transfusion Red blood cell
0
1
Fresh frozen plasma
0
0
Prothrombin time [%]
103 (73–129)
98 (76–121)
0.438
DGE (grade B, C)
3
2
0.579
APTT [%]
109 (65–144)
110 (69–136)
0.868
12
6
0.856
Fibrinogen [mg/dL]
308.5 (204–673)
389 (188–501)
0.161
Clavien–Dindo score (IIIa)
Platelet count [×103/mL]
235 (114–364)
197 (139–349)
0.877
Note; the continuous variables are shown as median (range). IPMN, intraductal papillary mucinous neoplasm; ASA PS, American society of anesthesiologists physical status; MPD, main pancreatic duct; APPT, activated partial thromboplastin time.
Note; the continuous variables are shown as median (range). SSPPD, subtotal stomach preserving pancreatoduodenectomy; PD, pancreatoduodenectomy; PV, portal vein; POPF, postoperative pancreatic fistula; DGE, delayed gastric emptying. Bold, p < 0.05.
Table 3 Multiple regression analysis of preoperative coagulation
parameters for intraoperative blood loss
correlated with intraoperative blood loss (Table 3). The intraoperative blood loss was estimated to increase by 8.46 mL if preoperative FXIII activity decreased by 1%. Dynamics of perioperative FXIII activity and other coagulation factors The levels of all examined coagulation parameters on POD 1 was significantly lower compared with the preoperative levels (Fig. 1). Although the levels of PT%, APTT%, fibrinogen, and platelet count recovered to the preoperative levels on POD 7, the levels of FXIII activity on POD 7 did not recover to the preoperative levels and were significantly lower than those before surgery. When patients were dichotomized by the levels of preoperative FXIII activity by 70%, the FXIII activities on POD 1 and POD 7 were significantly higher among the patients with preoperative FXIII activities 70% than in those with preoperative FXIII activities <70%. The FXIII activities on POD 1 and POD 7 were significantly lower than the preoperative activities irrespective of the normality of the preoperative FXIII activity. The FXIII activities were not correlated with the levels of PT%, APTT%, fibrinogen, or platelet count (data not shown). HPB 2017, -, 1–6
Parameters
Regression coefficient
95% CI (L, U)
SE
P value
FXIII [%]
−8.46
−16.07, −0.84
3.75
0.031
Prothrombin time [%]
1.77
−16.81, 20.24
9.15
0.848
APTT [%]
−2.20
−12.00, 7.53
4.8
0.647
Fibrinogen [mg/dL]
0.14
−1.79, 2.06
0.95
0.888
Platelet count [×103/mL]
0.109
−3.53, 3.75
1.79
0.952
95% CI (L, U), 95% confidence interval (lower confidence limit, upper confidence limit); SE, standard error; APTT, activated partial thromboplastin time. Bold, p < 0.05.
Discussion This study revealed that the proportions of patients with low preoperative FXIII activity (<70%) were unexpectedly high (35%) among the patients who underwent pancreatoduodenectomy. We also found that low FXIII activity was associated with an increased intraoperative blood loss in the patients who
© 2017 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Watanabe N, et al., Clinical influence of preoperative factor XIII activity in patients undergoing pancreatoduodenectomy, HPB (2017), http://dx.doi.org/10.1016/j.hpb.2017.07.002
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Figure 1 The perioperative dynamics of coagulation markers (FXIII, PT%, APTT%, fibrinogen, and platelet count) in patients who underwent
pancreatoduodenectomy. The dynamics of FXIII activity was also shown according to the dichotomized FXIII activities (70%, open circles with solid line; <70%, open squares with dotted line). *, P < 0.05 vs. preoperative values; †, P < 0.05 vs. FXIII <70%
underwent pancreatoduodenectomy. Regarding postoperative complications including pancreatic fistula and delayed gastric emptying, there were no differences between the patients with low and normal FXIII activities. FXIII is one of the main contributors during the final phase of the clotting cascade because it cross-links fibrin monomers.8,9 In HPB 2017, -, 1–6
clinical settings, FXIII deficiency occurs as a congenital condition as well as an acquired condition. Highly invasive surgeries that are accompanied by massive bleeding are among the most common medical conditions that elicit acquired FXIII deficiency due to a decreased synthesis and over-consumption of FXIII.22 Several studies have reported associations of FXIII deficiency
© 2017 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Watanabe N, et al., Clinical influence of preoperative factor XIII activity in patients undergoing pancreatoduodenectomy, HPB (2017), http://dx.doi.org/10.1016/j.hpb.2017.07.002
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and bleeding complications in abdominal, cardiovascular, and neurological surgeries.11–15 On the other hand, there are some reports showing no relationships between FXIII activity and perioperative bleeding in orthopedic, neurological, or cardiopulmonary bypass surgeries.23,24 The impact of preoperative FXIII activities on the intra- and postoperative outcomes in patients undergoing pancreatoduodenectomy has not been investigated. In this study, we found that patients with low preoperative FXIII activities experienced greater intraoperative blood loss during pancreatoduodenectomy. With multiple regression analysis including other coagulation-associated parameters, low preoperative FXIII activities was the only factor correlating with intraoperative blood loss. Although several studies have reported an association between decreased FXIII activity and hemorrhagic tendencies, the present study is the first report to demonstrate this association in patients undergoing pancreatoduodenectomy. In addition to clot formation, FXIII also has an important role in wound healing or tissue repair.10,25 It is well known that patients with congenital FXIII deficiencies exhibit impaired wound healing. In the acquired condition, Saeki et al. reported an association between decreased postoperative FXIII activity and anastomotic insufficiency in esophagectomy patients.26 Pancreatic fistula is major complication following pancreatoduodenectomy, and the administration of an FXIII concentrate for patients with intractable pancreatic fistula with decreased FXIII activity is approved by the health insurance system in Japan. However, in this study, there was no difference between the patients with low and normal FXIII activities in terms of the incidences of postoperative pancreatic fistula. The incidence of pancreatic fistula following pancreatoduodenectomy is affected by gender,27 body mass index,28 pancreatic texture,27,29,30 and the main pancreatic duct diameter.30 The influences of these clinical factors on the incidences of pancreatic fistula may be superior to that of FXIII activity. The present study also demonstrated the perioperative dynamics of FXIII activity, which has not been reported before, in patients undergoing pancreatoduodenectomy. We did not transfuse fresh frozen plasma in the perioperative period. Therefore, the results reflect the real influence of the surgical intervention on the level of FXIII activity. Regarding the preoperative FXIII levels, the proportions of patients with abnormally low FXIII activity before surgery were unexpectedly high. A number of asymptomatic patients with low FXIII activity may not be recognized because measurement of FXIII activity is not included in routine preoperative examinations. The liver is a major producer of FXIII, and biliary obstructions due to cholangiocarcinomas or pancreatic head carcinomas may deteriorate liver function and decrease FXIII production. However, all patients included in this study had normal liver function and normal serum bilirubin levels before surgery because preoperative biliary decompression in cases of biliary obstruction is routinely performed at our institution. HPB 2017, -, 1–6
Therefore, the reason for the high rate of low FXIII activities in the patients undergoing pancreatoduodenectomy is unknown. To clarify this issue, further large-scale data collection is necessary. The levels of coagulation parameters commonly decrease on POD 1 in major abdominal surgery. However, these levels generally recover over the postoperative course. It is noteworthy that the FXIII levels substantially decreased on POD 1 and remained at low levels until POD 7, although other coagulation parameters on POD 7 were recovering to preoperative levels. This observation may be partly explained by the relatively long half-life (7–14 days) of FXIII compared with other coagulation factors (indicating slow turnover). In other words, once FXIII activity is deteriorated, it is hard to recover without an intravenous supplementation. Nevertheless, it is also intriguing that we did not observe any specific relationship between the low FXIII activity after surgery and postoperative complications (data not shown). Benefit of FXIII supplementation in patients with low FXIII activity after surgery should be clarified in future study. In conclusion, a relatively high proportion of patients undergoing pancreatoduodenectomy exhibited abnormally low preoperative FXIII activity. Preoperative FXIII deficiency may increase intraoperative blood loss during pancreatoduodenectomy. Therefore, in patients with low FXIII activity before surgery, preoperative FXIII administration could be a useful option for reducing intraoperative blood loss. But this hypothesis should be tested in a randomized clinical trial. Conflict of interests None declared.
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© 2017 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Watanabe N, et al., Clinical influence of preoperative factor XIII activity in patients undergoing pancreatoduodenectomy, HPB (2017), http://dx.doi.org/10.1016/j.hpb.2017.07.002
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© 2017 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Watanabe N, et al., Clinical influence of preoperative factor XIII activity in patients undergoing pancreatoduodenectomy, HPB (2017), http://dx.doi.org/10.1016/j.hpb.2017.07.002
http://dx.doi.org/10.1016/j.hpb.2017.07.002
ORIGINAL ARTICLE
Clinical influence of preoperative factor XIII activity in patients undergoing pancreatoduodenectomy Nobuyuki Watanabe, Yukihiro Yokoyama, Tomoki Ebata, Gen Sugawara, Tsuyoshi Igami, Takashi Mizuno, Junpei Yamaguchi & Masato Nagino Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
Abstract Background: The influence of decreased factor XIII (FXIII) activity on perioperative bleeding has been reported in some surgical procedures. The purposes of this study were to investigate the perioperative dynamics of FXIII in patients undergoing pancreatoduodenectomy and to clarify the effects of low preoperative FXIII activity on intraoperative bleeding and postoperative complications. Methods: Total of 43 patients who underwent a pancreatoduodenectomy were enrolled. The perioperative FXIII activities were measured, and their associations with intraoperative bleeding and postoperative outcomes were analyzed. Results: Fifteen patients (35%) had low FXIII activities (<70%, lower than the institutional normal range). The patients with preoperative FXIII activities <70% experienced significantly greater blood loss (median, 1309 mL) during surgery compared to those with FXIII levels of 70% (median, 710 mL) (p = 0.001). The postoperative morbidity rates, including pancreatic fistula, were comparable between the patients with FXIII activities <70% and those with FXIII activities 70%. The FXIII levels substantially decreased on postoperative day 1 and remained at low levels until postoperative day 7. Conclusion: Unexpectedly high proportions of patients undergoing pancreatoduodenectomy had low preoperative FXIII activities. Preoperative FXIII deficiency may increase intraoperative bleeding but had no influence on the postoperative outcomes. Received 24 March 2017; accepted 2 July 2017
Correspondence Yukihiro Yokoyama, Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan. E-mail: yyoko@med. nagoya-u.ac.jp
Introduction Surgical resection is the only method for curing hepatopancreato-biliary (HPB) malignancies. Although a certain amount of intraoperative blood loss is inevitable in HPB surgery, excessive blood loss may lead to blood transfusions and severe postoperative complications. Indeed, several studies have indicated an association between intraoperative blood loss and postoperative complications.1,2 Additionally, some studies have claimed that perioperative blood transfusions have adverse influences on postoperative morbidity and tumor recurrence.3–7 Factor XIII (FXIII) is a key factor that functions at the end of the coagulation cascade by cross-linking fibrin monomers into stable polymers and counteracting fibrinolytic degradation.8,9 FXIII also This paper has not been presented in any meetings previously.
HPB 2017, -, 1–6
plays an important role in wound healing.10 Some studies have reported associations of FXIII activity with perioperative bleeding in cardiac,11,12 gastrointestinal,13 and neurologic surgeries.14,15 However,littleisknownabouttheroleofperioperativeFXIIIactivityinHPB surgeriesparticularly pancreatoduodenectomy. The purpose of the present study was to investigate the perioperative dynamics of FXIII in patients undergoing pancreatoduodenectomy and to clarify whether a preoperative deterioration of FXIII activity was associated with intraoperative blood loss or postoperative complications in these patients.
Methods Patients The study was approved by the ethical review board of the Nagoya University Hospital and was registered with the
© 2017 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Watanabe N, et al., Clinical influence of preoperative factor XIII activity in patients undergoing pancreatoduodenectomy, HPB (2017), http://dx.doi.org/10.1016/j.hpb.2017.07.002
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University Hospital Medical Information Network (registration No. UMIN000014580). Between September 2014 and August 2016, a total of 45 patients who underwent a pancreatoduodenectomy at the Division of Surgical Oncology, Department of Surgery, Nagoya University Hospital, were enrolled. Patients who were administered any anticoagulants before and after surgery were excluded. Written informed consent was obtained from each patient prior to enrollment in the study. Perioperative management Preoperative biliary drainage was performed when obstructive jaundice was confirmed. The externally drained bile was replaced orally or via administration through a nasoduodenal tube.16 The operations were performed when the total serum bilirubin decreased to less than 2 mg/dL. Perioperative antimicrobial prophylaxis was performed immediately before surgery and every 4–12 h (the intervals were determined according to the half-lives of the antimicrobials) during and after surgery (until 2 days after surgery). Cefazolin was generally selected for the patients without external biliary drainage. In patients with preoperative external biliary drainage, the type of antimicrobial was selected according to the results of a drained bile culture.17 The surgeons were blinded to the preoperative FXIII activity results at the time of operation. The replacement of FXIII was not allowed until postoperative day (POD) 7. Surgical techniques In general, we performed subtotal stomach-preserving pancreatoduodenectomies. Pancreatojejunostomy was performed using the duct-to-mucosa anastomosis with modified Blumgart method.18 A pancreatic duct drainage tube was inserted into the main pancreatic duct of the remnant pancreas, and the tube was exteriorized through the end of the blind loop of the jejunum. Blood sampling and data collection Blood samples for analysis were obtained within 1 week before surgery and on PODs 1 and 7. We measured the FXIII activity, prothrombin time % (PT%), activated partial thromboplastin time % (APTT%), fibrinogen level, and complete blood count. All laboratory tests were performed according to the protocol of the manufacturer. FXIII activity was measured via the synthetic substrate method (JCA-EM1650, JEOL Ltd., Tokyo, Japan), with a reference value of 70–140%. APTT% (STA-PTT Automate; Roche) and fibrinogen (STA-Fibrinogen; Roche) were measured using the clotting method. Preoperative low FXIII activity was defined as <70% based on the previous reports.11,14 This cut-off value is also used as lower limit of normal range of FXIII activity in our institution. The data for all participants were prospectively collected. The preoperative characteristics, including the patient’s age, gender, body mass index (BMI), preoperative diagnosis, American Society of Anesthesiologists physical status (ASA PS) classification,
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diabetes mellitus, and main pancreatic duct diameter measured by multiple-detector computed tomography before surgery were recorded. Intraoperative parameters, such as the surgical procedure, operation time, and blood loss, were also recorded. Intraoperative blood loss was calculated by weighing blood soaked gauze and measuring the amount of blood in suction bottles. Postoperative complications that occurred within 28 days after surgery were monitored and classified according to the Clavien–Dindo classification of surgical complications.19 Postoperative pancreatic fistula and delayed gastric emptying were diagnosed and classified based on the definitions of the International Study Group of Pancreatic Surgery.20,21 The incidences of intraoperative and postoperative transfusions were also recorded. Packed red blood cells were usually given when the hemoglobin decreased to <7 g/dl, and fresh frozen plasma was given when the PT%/APTT% value decreased to <40% or bloody fluid was found from the abdominal drains. Statistics The results are expressed as the medians (ranges) for the continuous data. The perioperative dynamics of FXIII activity are illustrated in line graphs with the means and standard deviations. The statistical analyses were performed using the Mann– Whitney U test, dependent t-test, c2 test, or Fisher’s exact probability test as appropriate. A multiple regression analysis was used to identify independent risk factors of intraoperative blood loss. A P value < 0.05 was considered statistically significant.
Results Preoperative FXIII activities and perioperative variables Among total of 45 patients participated in the study, two patients who were intraoperatively diagnosed as having an unresectable tumor were excluded. Therefore, 43 patients were finally analyzed. The preoperative FXIII activities were <70% (less than the institutional normal range) in 15 patients (35%) (Table 1). There were no significant differences between the patients with FXIII activities 70% and <70% in terms of preoperative characteristics. However, the median intraoperative blood loss in the patients with preoperative FXIII activities <70% was significantly greater than that in the patients with preoperative FXIII activities 70% (P = 0.001; Table 2). Additionally, the proportion of patients who received red blood cell or fresh frozen plasma transfusions during surgery was significantly greater among patients with preoperative FXIII activities <70% than among patients with preoperative FXIII activities 70%. The occurrences of clinically significant postoperative pancreatic fistula, delayed gastric emptying, and major postoperative complications with Clavien–Dindo scores IIIa were all comparable between the two groups. A multiple regression analysis of preoperative coagulation parameters revealed that preoperative FXIII activities significantly
© 2017 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Watanabe N, et al., Clinical influence of preoperative factor XIII activity in patients undergoing pancreatoduodenectomy, HPB (2017), http://dx.doi.org/10.1016/j.hpb.2017.07.002
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Table 1 Preoperative characteristics of patients who underwent
Table 2 Intraoperative and postoperative variables in patients who
pancreatoduodenectomy
underwent pancreatoduodenectomy
Preoperative FXIII activity
P value
‡70% (n [ 28)
<70% (n [ 15)
Age [years]
63 (42–86)
71.5 (54–83)
0.149
Male gender
20
11
0.594
BMI [kg/m2]
21.7 (15.2–31.5)
21.2 (18.2–23.7)
0.333
Pancreatic cancer
10
5
IPMN
5
0
Bile duct cancer
9
7
Diagnosis
Ampullary cancer
0.344
4
Preoperative FXIII activity
P value
‡70% (n [ 28)
<70% (n [ 15)
SSPPD
27
15
PD
1
0
Combined PV resection
4
3
0.468
Operation time [min]
460 (270–698)
446 (339–727)
0.809
Blood loss [mL]
710 (204–2296)
1309 (323–4385)
0.001
Procedure
0.651
Intraoperative transfusion
3
ASA PS classification
0.564
Red blood cell
4
9
0.003
Fresh frozen plasma
1
6
0.005
0.349
Class 1
11
4
Class 2
16
10
Class 3
1
1
Diabetes mellitus
9
7
0.348
Biliary drainage
19
13
0.164
Cholangitis
8
7
0.235
Postoperative complications
MPD diameter [mm]
3.5 (1.8–10.2)
4.9 (1.8–19.3)
0.759
POPF (grade B, C)
6
4
0.488
Postoperative transfusion Red blood cell
0
1
Fresh frozen plasma
0
0
Prothrombin time [%]
103 (73–129)
98 (76–121)
0.438
DGE (grade B, C)
3
2
0.579
APTT [%]
109 (65–144)
110 (69–136)
0.868
12
6
0.856
Fibrinogen [mg/dL]
308.5 (204–673)
389 (188–501)
0.161
Clavien–Dindo score (IIIa)
Platelet count [×103/mL]
235 (114–364)
197 (139–349)
0.877
Note; the continuous variables are shown as median (range). IPMN, intraductal papillary mucinous neoplasm; ASA PS, American society of anesthesiologists physical status; MPD, main pancreatic duct; APPT, activated partial thromboplastin time.
Note; the continuous variables are shown as median (range). SSPPD, subtotal stomach preserving pancreatoduodenectomy; PD, pancreatoduodenectomy; PV, portal vein; POPF, postoperative pancreatic fistula; DGE, delayed gastric emptying. Bold, p < 0.05.
Table 3 Multiple regression analysis of preoperative coagulation
parameters for intraoperative blood loss
correlated with intraoperative blood loss (Table 3). The intraoperative blood loss was estimated to increase by 8.46 mL if preoperative FXIII activity decreased by 1%. Dynamics of perioperative FXIII activity and other coagulation factors The levels of all examined coagulation parameters on POD 1 was significantly lower compared with the preoperative levels (Fig. 1). Although the levels of PT%, APTT%, fibrinogen, and platelet count recovered to the preoperative levels on POD 7, the levels of FXIII activity on POD 7 did not recover to the preoperative levels and were significantly lower than those before surgery. When patients were dichotomized by the levels of preoperative FXIII activity by 70%, the FXIII activities on POD 1 and POD 7 were significantly higher among the patients with preoperative FXIII activities 70% than in those with preoperative FXIII activities <70%. The FXIII activities on POD 1 and POD 7 were significantly lower than the preoperative activities irrespective of the normality of the preoperative FXIII activity. The FXIII activities were not correlated with the levels of PT%, APTT%, fibrinogen, or platelet count (data not shown). HPB 2017, -, 1–6
Parameters
Regression coefficient
95% CI (L, U)
SE
P value
FXIII [%]
−8.46
−16.07, −0.84
3.75
0.031
Prothrombin time [%]
1.77
−16.81, 20.24
9.15
0.848
APTT [%]
−2.20
−12.00, 7.53
4.8
0.647
Fibrinogen [mg/dL]
0.14
−1.79, 2.06
0.95
0.888
Platelet count [×103/mL]
0.109
−3.53, 3.75
1.79
0.952
95% CI (L, U), 95% confidence interval (lower confidence limit, upper confidence limit); SE, standard error; APTT, activated partial thromboplastin time. Bold, p < 0.05.
Discussion This study revealed that the proportions of patients with low preoperative FXIII activity (<70%) were unexpectedly high (35%) among the patients who underwent pancreatoduodenectomy. We also found that low FXIII activity was associated with an increased intraoperative blood loss in the patients who
© 2017 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Watanabe N, et al., Clinical influence of preoperative factor XIII activity in patients undergoing pancreatoduodenectomy, HPB (2017), http://dx.doi.org/10.1016/j.hpb.2017.07.002
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Figure 1 The perioperative dynamics of coagulation markers (FXIII, PT%, APTT%, fibrinogen, and platelet count) in patients who underwent
pancreatoduodenectomy. The dynamics of FXIII activity was also shown according to the dichotomized FXIII activities (70%, open circles with solid line; <70%, open squares with dotted line). *, P < 0.05 vs. preoperative values; †, P < 0.05 vs. FXIII <70%
underwent pancreatoduodenectomy. Regarding postoperative complications including pancreatic fistula and delayed gastric emptying, there were no differences between the patients with low and normal FXIII activities. FXIII is one of the main contributors during the final phase of the clotting cascade because it cross-links fibrin monomers.8,9 In HPB 2017, -, 1–6
clinical settings, FXIII deficiency occurs as a congenital condition as well as an acquired condition. Highly invasive surgeries that are accompanied by massive bleeding are among the most common medical conditions that elicit acquired FXIII deficiency due to a decreased synthesis and over-consumption of FXIII.22 Several studies have reported associations of FXIII deficiency
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and bleeding complications in abdominal, cardiovascular, and neurological surgeries.11–15 On the other hand, there are some reports showing no relationships between FXIII activity and perioperative bleeding in orthopedic, neurological, or cardiopulmonary bypass surgeries.23,24 The impact of preoperative FXIII activities on the intra- and postoperative outcomes in patients undergoing pancreatoduodenectomy has not been investigated. In this study, we found that patients with low preoperative FXIII activities experienced greater intraoperative blood loss during pancreatoduodenectomy. With multiple regression analysis including other coagulation-associated parameters, low preoperative FXIII activities was the only factor correlating with intraoperative blood loss. Although several studies have reported an association between decreased FXIII activity and hemorrhagic tendencies, the present study is the first report to demonstrate this association in patients undergoing pancreatoduodenectomy. In addition to clot formation, FXIII also has an important role in wound healing or tissue repair.10,25 It is well known that patients with congenital FXIII deficiencies exhibit impaired wound healing. In the acquired condition, Saeki et al. reported an association between decreased postoperative FXIII activity and anastomotic insufficiency in esophagectomy patients.26 Pancreatic fistula is major complication following pancreatoduodenectomy, and the administration of an FXIII concentrate for patients with intractable pancreatic fistula with decreased FXIII activity is approved by the health insurance system in Japan. However, in this study, there was no difference between the patients with low and normal FXIII activities in terms of the incidences of postoperative pancreatic fistula. The incidence of pancreatic fistula following pancreatoduodenectomy is affected by gender,27 body mass index,28 pancreatic texture,27,29,30 and the main pancreatic duct diameter.30 The influences of these clinical factors on the incidences of pancreatic fistula may be superior to that of FXIII activity. The present study also demonstrated the perioperative dynamics of FXIII activity, which has not been reported before, in patients undergoing pancreatoduodenectomy. We did not transfuse fresh frozen plasma in the perioperative period. Therefore, the results reflect the real influence of the surgical intervention on the level of FXIII activity. Regarding the preoperative FXIII levels, the proportions of patients with abnormally low FXIII activity before surgery were unexpectedly high. A number of asymptomatic patients with low FXIII activity may not be recognized because measurement of FXIII activity is not included in routine preoperative examinations. The liver is a major producer of FXIII, and biliary obstructions due to cholangiocarcinomas or pancreatic head carcinomas may deteriorate liver function and decrease FXIII production. However, all patients included in this study had normal liver function and normal serum bilirubin levels before surgery because preoperative biliary decompression in cases of biliary obstruction is routinely performed at our institution. HPB 2017, -, 1–6
Therefore, the reason for the high rate of low FXIII activities in the patients undergoing pancreatoduodenectomy is unknown. To clarify this issue, further large-scale data collection is necessary. The levels of coagulation parameters commonly decrease on POD 1 in major abdominal surgery. However, these levels generally recover over the postoperative course. It is noteworthy that the FXIII levels substantially decreased on POD 1 and remained at low levels until POD 7, although other coagulation parameters on POD 7 were recovering to preoperative levels. This observation may be partly explained by the relatively long half-life (7–14 days) of FXIII compared with other coagulation factors (indicating slow turnover). In other words, once FXIII activity is deteriorated, it is hard to recover without an intravenous supplementation. Nevertheless, it is also intriguing that we did not observe any specific relationship between the low FXIII activity after surgery and postoperative complications (data not shown). Benefit of FXIII supplementation in patients with low FXIII activity after surgery should be clarified in future study. In conclusion, a relatively high proportion of patients undergoing pancreatoduodenectomy exhibited abnormally low preoperative FXIII activity. Preoperative FXIII deficiency may increase intraoperative blood loss during pancreatoduodenectomy. Therefore, in patients with low FXIII activity before surgery, preoperative FXIII administration could be a useful option for reducing intraoperative blood loss. But this hypothesis should be tested in a randomized clinical trial. Conflict of interests None declared.
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© 2017 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Watanabe N, et al., Clinical influence of preoperative factor XIII activity in patients undergoing pancreatoduodenectomy, HPB (2017), http://dx.doi.org/10.1016/j.hpb.2017.07.002