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fibrinogen degradation products without increase of plasmin-α2-plasmin inhibitor complex after hepatectomy for hepatocellular carcinoma
RESEARCH 57; 289-300, 1990 0049-3848/90 $3.00 t .OO Printed in the USA. Copyright (c) 1990 Pergamon Press plc. All rights reserved.
THROMBOSIS
INCREASED FIBRIN/FIBRINOGEN DEGRADATION OF PLASMIN-dt-PLASMIN INHIBITOR COMPLEX HEPATOCELLULAR CARCINOMA
Shigeaki Takeda, Hidenori Kohji Okamoto and Keiichi
Katoh, Ohsato
Akira
PRODUCTS WITHOUT AFTER HEPATECTOMY
INCREASE FOR
Takaki,
From the Department of Surgery I, University and Environmental Health, School of Medicine, Japan
of Occupational Kitakyushu 807,
(Received 3.7.1989; accepted in revised form 6.11.1989 by Editor H. Yamazaki)
ABSTRACT To clarify the meaning of increased serum fibrin/fibrinogen degradation products (FDP) in the postoperative period of hepatectomy, blood coagulation and fibrinolysis were studied using recently devised laboratory assays of a group of 30 patients with hepatocellular carcinoma. Twenty of these cases were associated with liver cirrhosis. As a control group, 15 patients with colorectal carcinoma without liver diseases were also selected. In the early postoperative period following hepatectomy, a'hypercoagulable state designated as intravascular thrombin generation was confirmed from the finding of increased plasma levels of fibrinopeptide A (FPA). Fibrinopeptide BR 15-42 (BR 15-42) in the plasma also increased immediately after the peak of FPA, followed by a gradual decline in BP 15-42 levels. On the other hand, FDP in the serum increased significantly rather late in the postoperative period following hepatectomy without increased levels of plasmin-&-plasmin inhibitor complex. However, postoperative increase of fibrin/fibrinogen degradation products-D (FDP-D) was modest and not different from the colectomy group. Therefore, the relevance of intravascular coagulation in the hepatectomy for the patients with liver cirrhosis seems not to be significant, and then such an increase of FDP in the serum seems to be related to other mechanisms.
Key
words
:
Hepatectomy; Fibrin/fibrinogen products (FDP); Intravascular Liver cirrhosis. 289
degradation coagulation;
290
FDP AFTER
HEPATECTOMY
Vol. 57, No. 2
INTRODUCTION Postoperative periods of hepatectomy in patients with hepatocellular carcinoma are frequently associated with hemostatic abnormalities, as well as liver dysfunction. These patients may develop fatal bleeding tendencies unless proper treatment was initiated. Hemostatic findings from laboratory tests are similar to those seen in disseminated intravascular coagulation (DIC) and are approximately proportional to the extent of resection and/or the severity of combined liver diseases (1, 2). Decreased levels of vitamin K dependent clotting factors and increased levels of fibrin/fibrinogen degradation products (FDP) are the most common findings in this postoperative periods (2). Despite extensive investigations, the occurrence of intravascular coagulation in severe liver diseases is still controversial (3-6). This controversy may be caused, in part, by the fact that most of the conventional laboratory tests used in this issue have quite high sensitivities, but rather low specificities for detecting intravascular coagulation and fibrinolysis (7). A variety of sensitive procedures with high specificity have been devised for evaluating the interaction between thrombin, plasmin (Pm) and fibrinogen/fibrin. These procedures may be useful in providing insights into the pathophysiology of intravascular coagulation (8-11) and its relevance in severe liver diseases. The present study was performed to clarify the meaning of coaguespecially increased fibrin/fibrinogen lation abnormalities, degradation products (FDP) in serum after hepatectomy for hepatocellular carcinoma, by using several newly developed assay methods for measuring fibrinopeptide A (FPA), fibrinopeptide B/3 fibrin/fibrinogen degradation products-D 15-42 (BP 15-42), (FDP-D), &-plasmin inhibitor (&-PI) and Pm-&-PI complex.
PATIENTS
AND
METHODS
Patients: This study consisted of a consecutive 30 Japanese patients with hepatocellular carcinoma seen at the Department of Surgery I of the University of Occupational and Environmental Health, School of Medicine, Kitakyusyu, Japan, during the period The mean age was 59.2 f 11.2 (SD) from Feb. 1983 to Mar. 1986. / female ratio was 23 / 7. years (range 35 - 81) and the male The grade of hepatic dysfunction was Child's A in 22 patients, B according to the Child's classification (12). in 8 and C in none, The mean value of 15 minutes removal rate of indocyanine green (ICG R15) was 21.5 f 10.5 (SD) per cent (range 4.5 - 41.5). Twenty-five patients (73 per cent) showed abnormal values of ICG R15 above normal range of 10 per cent. Histologically combined liver cirrhosis was seen in 20 (67 per cent) and liver fibrosis or chronic hepatitis was seen in 7 (23 per cent) of the 30 patients. The mean weight of resected liver was 275 f 235 (SD) g Performed operation, operating time, operative (range 25 - 870). blood loss and operative blood replacement are shown in Tables 1 morbidity and mortality, there were and 2. As to postoperative bleeding in one three severe complications i.e. intraoperative upper gastrointestinal bleeding in two, and hepatic patient, died within 1 month after failure in two. Two of the patients which produced an operative mortality rate of 6.7 persurgery,
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FDPAFTERHEPATECTOMY
291
cent. As a control, 15 patients with colorectal carcinoma who had undergone colectomy or amputation of the rectum were selected. None of the patients in the control group had combin,ed liver diseases. Their clinical data for both groups were listed in Tables 1 and 2. No clinical deep vein thrombosis occurred in either the study group or the control group during this study.
TABLE
1
Details of Operative Procedure Performed on Hepatocellular Carcinoma and on 15 Patients Carcinoma Hepatocellular Performed hepatic hepatic hepatic hepatic
Colorectal
carcinoma
operation
No.
Performed
of
lobectomy segmentectomy subsegmentectomy local resection
TABLE Intraoperative Clinical Mean t SD (Range).
No.
of
patients
Operating
time
(hr)
blood loss during operation (g) blood during
transfusion operation
(g)
operation
of
No. of patients
rectum
3
2
Data.
Hepatocellular
carcinoma
colectomy amputation
4 10 12 4
30 Patients with with Colorectal
Results
carcinoma
were
Expressed
Coloretal
as
carcinoma
30
15
4.8 f 2.1 (1.2-9.3)
3.3 f 0.8 (2.4-5.0)
2789.7 f 2621.0 (80-13,000)
354.0 f 289.0 (80-1,100)
2852.0 f 1678.6 (840-7,500) n=24
550.0 f 87.0 (400-900) n=7
Methods : Blood samples were taken early in the morning preoperatively and early in the morning on postoperative days 1, 3, 5, 7, 14 and 21. In the control group, blood sampling was not performed on day 21. Citrated plasma was collected using vacutainer tubes (Jintan, Tokyo, Japan) containing l/10 volume of 0.13 mol/l sodium citrate and stored for the analysis of FDP-0, plasminogen (Pmg), &- PI and Pm-&-PI complex at -7O.C. Blood samples for determination of serum FDP was withdrawn into vacutainer tubes containing batroxobin 0.8 ug, thrombin 5 N.I.H., aprotinin 250 units and CaC12 0.3 mg. Blood samples for determination of FPA and Bp15-42 were withdrawn into vacutainer tubes containing 0.4 ml of heparin 500 units/ml and aprotinin 10,000 units/ml and stored at -70°C until analysis.
292
FDP AFTER HEPATECTOMY
Vol. 57, No. 2
Fibrinogen (Fbg) was measured by the method of Ratnoff and Menzie. Serum FDP was measured using latex agglutination test kit (Teikoku-zoki, Tokyo). Fbg and serum FDP were determined on the day the samples were taken. Plasma FDP-D was measured using latex turbidimetric immunoassay kits (Daiichi-kagaku, Tokyo). FPA and BD 15-42 were measured in SRL laboratory (Tokyo) using IMCO radioimmunoassay kits separately. Pmg was measured by the use of chromogenic assay kits (Daiichi-kagaku, Tokyo). AZ-PI and Pm-AZ-PI complex were measured immunologically by the method of one step sandwich method using assay kits of TD 80 and TD 80C (Teijin, Tokyo) respectively, These kits were kindly supplied by the Tel Jin company. Liver function tests, including prothrombin activity (PT), albumin (Alb) and total cholesterol (T. chol), were measured by In the control group, Alb means of standard laboratory methods. and T. chol were not measured. Statistical analysis was carried out through appropriate use of the Student's t-test and chi-square statistic. A value of P< 0.05 was considered to be statistically significant.
RESULTS The results were presented in Tables 3 and 4 and in Figure 1. These results are summarized briefly below. 1) Fbg, FPA and B/, 15-42 : Postoperative increase of Fbg levels in hepatectomy group was mild and of short durati0.n. The maximum mean value was 317.4 mg/dl on day 3. By other postoperative days, the mean value was not significantly different from the preoperative value. However, this increase in colectomy group was remarkable. Significantly elevated levels were observed on days 3, 5, and 7. Postoperative FPA levels in the hepatectomy group increased for these days were 6.8 + markedly on days 1 and 3. Mean values 9.6 and 7.4 f 5.9 pmol/ml respectively. The values gradually decreased to preoperative level. On the other hand, the postoperative increase of FPA in the colectomy group pas mild and Significant differences were lower than in the hepatectomy group. seen between the two groups on days 1, 3 and 7 (see Fig. 1). Postoperative BP 15-42 levels also increased significantly in the hepatectomy group than in the colectomy group. A maximum value of 6.6 + 2.8 pmol/ml for the hepatectomy group was reached was slightly later than the peak value for FPA on day 5, which differences between the which occurred on day 3. Significant hepatectomy group and the colectomy group were seen on days 3, 7 and 14 postoperatively (see Fig. 1). increase of 2) Serum FDP and plasma FDP-D : The postoperative serum FDP was remarkable in both groups when compared with their Those in the hepatectomy group showed a sigpreoperative levels. nificant increase as compared with the colectomy group on days 5, mean values shown on days 7 and 14 were 7, and 14. The maximum 18.4 f 10.9 and 19.4 * 16.2 ug/ml respectively (see Fig. 1) Postoperative levels of FDP-D also increased significantly in both groups when compared with their preoperative levels. But there were no significant differences between the hepatectomy
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FDPAFTERHEPATECTOMY
group and the colectomy any of the postoperative
group regarding days.
postoperative
293
the
amount
of
increase
on
day
levels (mean f SD) of FPA, FIG. 1. Pre- and postoperative complex in the hepatectomy Bn 15-42, FDP, FDP-D and Pm-& -PI group (o-0) and in the colectomy group (o--O). Each normal range BO 15-42: 0.4-1.3 pmol/ml, is as follows; FPA: 0.2-0.8 pmol/ml, O-O.62 pg/ml and Pm-.&-PI complex: FDP: O-5 fig/ml, FDP-D: 0.15-0.40 yg/ml. Significance of the difference of each pre- and postoperative value between the two groups are shown by * : p
group, 3) Pmg, &-PI and Pm-AZ-PI complex : In the hepatectomy preoperative levels of Pmg decreased moderately and the postoperative levels were also decreased significantly when compared Postoperative changes of Pmg levels for with the colectomy group. both groups were similar and significant decreases were observed on days 1 and 3.
FDP AFTER HEPATECTOMY
294
Vol. 57, No. 2
levels of dp-PI in the hepatectomy Pre- and postoperative group also decreased significantly when compared with the colectomy group. The hepatectomy group did not show any significant postoperative change, on the other hand, the colectomy group showed a significant increase on day 3. Postoperative peak values of Pm-&-PI complex for both groups were observed on day 5, but the postoperative increase of Pm-X,-PI complex was not significant when compared with their preoperative levels. There were no significant differences between the groups regarding the amount of change in these values. 4) Liver function-tests : Postoperative levels of PT, Alb and T. chol were decreased significantly in the hehatectomy group on all postoperative days as compared to their preoperative levels. PT showed a significant decrease only on day 1 for the colectomy group. Alb and T. chol were not measured for the colectomy group (see Tables 3 and 4).
TABLE Pre- and and AZ,-PI, T. chol)
3
Postoperative Levels (Mean and Liver Function Tests in the Hepatectomy Group Postoperative 3rd 5th
Pre-op
1st
Fbg mg/dl (200400)
259.7 +77.0 n=30
225.0 k55.0 n=30
317.4** t85.3 n=30
285.3 k76.3 n=30
Pmg % (85-108)
79.0 t22.0 n=20
63.2* *15.8 n=20
58.9** k23.0 n=20
J2-p1
35.0 Wo"
(52-68)
35*1 ill.8 n=20
PT % (70-120)
79i15 n=30
Alb mg/dl (4.0-5.4)
chol mg/dl (125-240)
?,'
T.
(
f SD) of (PT, Alb
day 7th
Fbg, and
Pmg
14th
21th
273.2 t90.7 n=30
256.0 k83.9 n=30
213.0 k50.3 n=30
65.5 t20.7 n=20
74.0 *17.9 n=20
71.5 kl6.5 n=20
71.1 *18.8 n=20
35.9 t12.0 n=20
34.1 t13.4 n=20
33.9 k13.2 n=20
34.8 kl4.3 n=20
34.5 k7.6 n=20
57*11** n=30
58*28** n=30
6O-L29** n=30
52t30** n=30
43+32** n=30
3.69 to.35 n=30
3.53** iO.36 n=30
3.37** to.44 n=30
3.36** to.41 n=30
3.39** to.38 n=30
3.33** *0.43 n=30
3.35** *0.40 n=30
156.6 k26.3 n=30
115.8** ~26.0 n=30
118.0** *21.1 n=30
113.3** i25.6 n=30
115.8** k25.8 n=30
llO.l** *30.4 n=30
117.2** k32.8 n=30
1 : Normal Significance preoperative * : P (0.05,
40t14** n=30
ranges. of the difference was calculated between level and each postoperative level. ** : P< 0.01
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FDPAFTERHEPATECTOMY
TABLE Pre-
&-PI
Fbg mg/dI (200400) Pmg % (85-108)
ug/mI (52-68)
&-PI
PT % (70-120)
4.
and Postoperative Levels and PT in the Colectomy
Pre-op 353.0 *77.0 n=15
497.7** t85.2 n=15
99.6 t30.7 n=lO
60.4** il6.8 n=lO
76.0* t17.0 n=lO
55.1 i8.9 n=lO
54.0 *lo.7 n=lO
68.0** *lO.O n=lO
( ) : Normal Significance preoperative * : P
(Mean t Group.
Postoperative 3rd 5th
1st 375.4 *79.1 n=15
93*17 n=15
295
68*12** n=15
93*11 n=15
479.7* t78.6 n=15 82.6 t12.6 n=lO 62.0 t13.1 n=lO 94k18 n=15
SD)
of
Fbg,
day 7th
14th
438.4 *99.7 n=15
410.5 i103.3 n=15
95.1 t11.2 n=lO 60.9 i13.2 n=lO 88*21 n=15
Pmg,
100.5 t8.4 n=lO 59.1 t10.7 n=lO 87t16 n=15
ranges. of the difference was calculated between level and each postoperative level. ** : P(O.01
DISCUSSION The aim of the present study is to evaluate the signififibrin formation and cance of intravascular thrombin generation, its degradation in the postoperative period of hepatectomy for hepatocellular carcinoma associated with liver cirrhosis. Statistical analysis was performed on data collected through the use of recently developed laboratory assays of FPA (8), BE 15-42 (9,14), FDP-D (15), &-PI (16) and Pm-.&-PI complex (11). Data from the conventional assay of FDP (25) were also analyzed. FPA levels in blood samples have been postulated a-s an index of intravascular thrombin generation (13). Elevated FPA levels have been reported in association with several clinical disorders including postoperative period (8,13,17,19,20,21), indicating a hypercoagulable state. In the present study, FPA levels increased significantly in the early postoperative periods. Levels of BA 15-42, the earliest plasmic degradation products of fibrin, also increased immediately after the peak of FPA and then showed a gradual decline. Increase of BA 15-42 has been attributed to subsequent activation of fibrinolysis following the postoperative hypercoagulable state (22). The larger degree of operative injury of hepatectomy might be assessed by the longer operating time, the larger blood loss, and the larger amount of blood replacement as compared with those of colectomy (as illustrated in Table 1). It may be that a hypercoagulable state occurred only in the early postoperative period of hepatectomy, and that the magnitude of this state was larger for the hepatec-
296
tomy
FDP AFTER HEPATECTOMY
Vol. 57, No. 2
patients than for the colectomy patients. Circulating cross-linked fibrin derivatives are known to be specific markers of intravascular coagulation. Methods for immunological detections of X oligomers, D dimers and DD/E complexes in plasma and serum are now available (10,23). FOP-D assay used in this study reacts with D-dimers and D-monomers, but shows a fourto five-fold preference for D-dimers over D-monomers (15). FDP-D levels in plasma increased somewhat in the postoperative period of hepatectomy, but this increase was modest and not different from the increase for colectomy patients. Therefore, despite presence of a hypercoagulable state, intravascular coagulation was not apparent during this period of hepatectomy. This finding is consistent with previous reports that intravascular coagulation has not been a prominent feature among patients having various degree of liver diseases (18,24). On the other hand, FDP levels in serum did increase significantly rather late in the postoperative period for the hepatectomy patients in this study when measured by the conventional FDP assay method. This difference between measures of plasma FDP-D and serum FDP levels may be explained by the fact that the conventional FDP assay method is more reactive with the early and intermediate fragments of X and Y families than with the final fragments of D and E and also reacts with fragments of FDP derived from fibrinogenolysis and/or FDP derived from non-crosslinked fibrin (25,26). VanDeWalter et al have emphasized the significance of dysfunctional Fbg as a cause of elevated serum FDP levels in liver disease (27). In addition, early derivatives of FDP are known to be cleared from blood more slowly than are the late derivatives of FDP, and this clearing is due mostly to the reticuloendothelial system (RES) of the liver (28,29). Although we have no direct evidence of impairment of RES clearance in the present study, this function decreases among patients with liver cirrhosis markedly (28). This decrease is also proportional to the level of hepatocellular dysfunction as shown by the data of PT, Alb and T. chol in this study. Consequently it may be conceivable that serum FDP increased rather late in the postopera.tive period due not to DIC, but rather to delay in clearance of early derivatives of FDP. Furthermore this FDP may also have originated partly from defective polymerized Fbg/fibrin of dysfunctional Fbg during serum formation and/or from soluble fibrin monomer complex (4, 27). Decreased levels of &-PI have been known to cause accelerated fibrinolysis in severe diseases (16). The &-PI level in plasma is also known to increase as an acute phase reactant like but this increase is weak in response to surgical fibrinogen, trauma (30) such as was typical of the colectomy in this study. an increase of &-PI was not observed postoperatively However, probably indicating decreased synthesis in the hepatectomy group, recent reports based the analy-' in the liver. On the contrary, sis of several parameters have suggested that DIC could play an in liver cirrhosis (31,32). important role in decreasing X ,_-PI determination of Pm-&-PI complex is crucial for eValTherefore, uating fibrinolysis in severe liver diseases (11,33). Significant increase of this complex has been reported in patients with DIC (34,35). Postoperative increase of this complex in the hepatectomy group was not significant when compared with the preoperative It revealed a rather low level as compared to the coleClevels.
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FDP AFTER HEPATECTOMY
297
tomy group. Whereas, S/3 15-42 increased significantly after hepatectomy. This discrepancy between the values of the two indicators may be explained by the fact that Pm generated after hepatectomy more easily binds to fibrin and release BP 15-42 rather than binding to 4 -PI and forming Pm-Jr-PI complex:As a related mechanism, fibrin formed after hepatectomy in this study is thought to contain much lower level of da-PI as compared to the level of Pmg within the fibrin network. These lowered levels may contribute to enhanced fibrinolysis. The binding of Pmg into fibrin in &-PI deficient plasma has been shown to increase through structures which are called lysine binding sites (33). Such fibrin is easily dissolved by rather small amounts of Pm and then show significant increase of B/f 15-42. Therefore, since detected levels of Pm-&-PI complex in this series of elective hepatectomy were rather low, it is suggested that plasmin action may be limited to the local fibrinolysis in response to operative fibrin generation and that no obvious systemic fibrinolysis folDIC occurs in the uncomplicated postoperative conditions. lowing
ACKNOWLEDGMENT A part of the Intractable of Japan.
this study was supported Diseases of the Ministry
by a Research Grant from of Health and Welfare
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A. and BENNETT, B.: Plasmin-a2-antiplasmin in bleeding disorders characterized by primary or fibrinolysis. Brit. J. Hematol. 56, 545-56, 1984.
THROMBOSIS
INCREASED FIBRIN/FIBRINOGEN DEGRADATION OF PLASMIN-dt-PLASMIN INHIBITOR COMPLEX HEPATOCELLULAR CARCINOMA
Shigeaki Takeda, Hidenori Kohji Okamoto and Keiichi
Katoh, Ohsato
Akira
PRODUCTS WITHOUT AFTER HEPATECTOMY
INCREASE FOR
Takaki,
From the Department of Surgery I, University and Environmental Health, School of Medicine, Japan
of Occupational Kitakyushu 807,
(Received 3.7.1989; accepted in revised form 6.11.1989 by Editor H. Yamazaki)
ABSTRACT To clarify the meaning of increased serum fibrin/fibrinogen degradation products (FDP) in the postoperative period of hepatectomy, blood coagulation and fibrinolysis were studied using recently devised laboratory assays of a group of 30 patients with hepatocellular carcinoma. Twenty of these cases were associated with liver cirrhosis. As a control group, 15 patients with colorectal carcinoma without liver diseases were also selected. In the early postoperative period following hepatectomy, a'hypercoagulable state designated as intravascular thrombin generation was confirmed from the finding of increased plasma levels of fibrinopeptide A (FPA). Fibrinopeptide BR 15-42 (BR 15-42) in the plasma also increased immediately after the peak of FPA, followed by a gradual decline in BP 15-42 levels. On the other hand, FDP in the serum increased significantly rather late in the postoperative period following hepatectomy without increased levels of plasmin-&-plasmin inhibitor complex. However, postoperative increase of fibrin/fibrinogen degradation products-D (FDP-D) was modest and not different from the colectomy group. Therefore, the relevance of intravascular coagulation in the hepatectomy for the patients with liver cirrhosis seems not to be significant, and then such an increase of FDP in the serum seems to be related to other mechanisms.
Key
words
:
Hepatectomy; Fibrin/fibrinogen products (FDP); Intravascular Liver cirrhosis. 289
degradation coagulation;
290
FDP AFTER
HEPATECTOMY
Vol. 57, No. 2
INTRODUCTION Postoperative periods of hepatectomy in patients with hepatocellular carcinoma are frequently associated with hemostatic abnormalities, as well as liver dysfunction. These patients may develop fatal bleeding tendencies unless proper treatment was initiated. Hemostatic findings from laboratory tests are similar to those seen in disseminated intravascular coagulation (DIC) and are approximately proportional to the extent of resection and/or the severity of combined liver diseases (1, 2). Decreased levels of vitamin K dependent clotting factors and increased levels of fibrin/fibrinogen degradation products (FDP) are the most common findings in this postoperative periods (2). Despite extensive investigations, the occurrence of intravascular coagulation in severe liver diseases is still controversial (3-6). This controversy may be caused, in part, by the fact that most of the conventional laboratory tests used in this issue have quite high sensitivities, but rather low specificities for detecting intravascular coagulation and fibrinolysis (7). A variety of sensitive procedures with high specificity have been devised for evaluating the interaction between thrombin, plasmin (Pm) and fibrinogen/fibrin. These procedures may be useful in providing insights into the pathophysiology of intravascular coagulation (8-11) and its relevance in severe liver diseases. The present study was performed to clarify the meaning of coaguespecially increased fibrin/fibrinogen lation abnormalities, degradation products (FDP) in serum after hepatectomy for hepatocellular carcinoma, by using several newly developed assay methods for measuring fibrinopeptide A (FPA), fibrinopeptide B/3 fibrin/fibrinogen degradation products-D 15-42 (BP 15-42), (FDP-D), &-plasmin inhibitor (&-PI) and Pm-&-PI complex.
PATIENTS
AND
METHODS
Patients: This study consisted of a consecutive 30 Japanese patients with hepatocellular carcinoma seen at the Department of Surgery I of the University of Occupational and Environmental Health, School of Medicine, Kitakyusyu, Japan, during the period The mean age was 59.2 f 11.2 (SD) from Feb. 1983 to Mar. 1986. / female ratio was 23 / 7. years (range 35 - 81) and the male The grade of hepatic dysfunction was Child's A in 22 patients, B according to the Child's classification (12). in 8 and C in none, The mean value of 15 minutes removal rate of indocyanine green (ICG R15) was 21.5 f 10.5 (SD) per cent (range 4.5 - 41.5). Twenty-five patients (73 per cent) showed abnormal values of ICG R15 above normal range of 10 per cent. Histologically combined liver cirrhosis was seen in 20 (67 per cent) and liver fibrosis or chronic hepatitis was seen in 7 (23 per cent) of the 30 patients. The mean weight of resected liver was 275 f 235 (SD) g Performed operation, operating time, operative (range 25 - 870). blood loss and operative blood replacement are shown in Tables 1 morbidity and mortality, there were and 2. As to postoperative bleeding in one three severe complications i.e. intraoperative upper gastrointestinal bleeding in two, and hepatic patient, died within 1 month after failure in two. Two of the patients which produced an operative mortality rate of 6.7 persurgery,
Vol.57, No. 2
FDPAFTERHEPATECTOMY
291
cent. As a control, 15 patients with colorectal carcinoma who had undergone colectomy or amputation of the rectum were selected. None of the patients in the control group had combin,ed liver diseases. Their clinical data for both groups were listed in Tables 1 and 2. No clinical deep vein thrombosis occurred in either the study group or the control group during this study.
TABLE
1
Details of Operative Procedure Performed on Hepatocellular Carcinoma and on 15 Patients Carcinoma Hepatocellular Performed hepatic hepatic hepatic hepatic
Colorectal
carcinoma
operation
No.
Performed
of
lobectomy segmentectomy subsegmentectomy local resection
TABLE Intraoperative Clinical Mean t SD (Range).
No.
of
patients
Operating
time
(hr)
blood loss during operation (g) blood during
transfusion operation
(g)
operation
of
No. of patients
rectum
3
2
Data.
Hepatocellular
carcinoma
colectomy amputation
4 10 12 4
30 Patients with with Colorectal
Results
carcinoma
were
Expressed
Coloretal
as
carcinoma
30
15
4.8 f 2.1 (1.2-9.3)
3.3 f 0.8 (2.4-5.0)
2789.7 f 2621.0 (80-13,000)
354.0 f 289.0 (80-1,100)
2852.0 f 1678.6 (840-7,500) n=24
550.0 f 87.0 (400-900) n=7
Methods : Blood samples were taken early in the morning preoperatively and early in the morning on postoperative days 1, 3, 5, 7, 14 and 21. In the control group, blood sampling was not performed on day 21. Citrated plasma was collected using vacutainer tubes (Jintan, Tokyo, Japan) containing l/10 volume of 0.13 mol/l sodium citrate and stored for the analysis of FDP-0, plasminogen (Pmg), &- PI and Pm-&-PI complex at -7O.C. Blood samples for determination of serum FDP was withdrawn into vacutainer tubes containing batroxobin 0.8 ug, thrombin 5 N.I.H., aprotinin 250 units and CaC12 0.3 mg. Blood samples for determination of FPA and Bp15-42 were withdrawn into vacutainer tubes containing 0.4 ml of heparin 500 units/ml and aprotinin 10,000 units/ml and stored at -70°C until analysis.
292
FDP AFTER HEPATECTOMY
Vol. 57, No. 2
Fibrinogen (Fbg) was measured by the method of Ratnoff and Menzie. Serum FDP was measured using latex agglutination test kit (Teikoku-zoki, Tokyo). Fbg and serum FDP were determined on the day the samples were taken. Plasma FDP-D was measured using latex turbidimetric immunoassay kits (Daiichi-kagaku, Tokyo). FPA and BD 15-42 were measured in SRL laboratory (Tokyo) using IMCO radioimmunoassay kits separately. Pmg was measured by the use of chromogenic assay kits (Daiichi-kagaku, Tokyo). AZ-PI and Pm-AZ-PI complex were measured immunologically by the method of one step sandwich method using assay kits of TD 80 and TD 80C (Teijin, Tokyo) respectively, These kits were kindly supplied by the Tel Jin company. Liver function tests, including prothrombin activity (PT), albumin (Alb) and total cholesterol (T. chol), were measured by In the control group, Alb means of standard laboratory methods. and T. chol were not measured. Statistical analysis was carried out through appropriate use of the Student's t-test and chi-square statistic. A value of P< 0.05 was considered to be statistically significant.
RESULTS The results were presented in Tables 3 and 4 and in Figure 1. These results are summarized briefly below. 1) Fbg, FPA and B/, 15-42 : Postoperative increase of Fbg levels in hepatectomy group was mild and of short durati0.n. The maximum mean value was 317.4 mg/dl on day 3. By other postoperative days, the mean value was not significantly different from the preoperative value. However, this increase in colectomy group was remarkable. Significantly elevated levels were observed on days 3, 5, and 7. Postoperative FPA levels in the hepatectomy group increased for these days were 6.8 + markedly on days 1 and 3. Mean values 9.6 and 7.4 f 5.9 pmol/ml respectively. The values gradually decreased to preoperative level. On the other hand, the postoperative increase of FPA in the colectomy group pas mild and Significant differences were lower than in the hepatectomy group. seen between the two groups on days 1, 3 and 7 (see Fig. 1). Postoperative BP 15-42 levels also increased significantly in the hepatectomy group than in the colectomy group. A maximum value of 6.6 + 2.8 pmol/ml for the hepatectomy group was reached was slightly later than the peak value for FPA on day 5, which differences between the which occurred on day 3. Significant hepatectomy group and the colectomy group were seen on days 3, 7 and 14 postoperatively (see Fig. 1). increase of 2) Serum FDP and plasma FDP-D : The postoperative serum FDP was remarkable in both groups when compared with their Those in the hepatectomy group showed a sigpreoperative levels. nificant increase as compared with the colectomy group on days 5, mean values shown on days 7 and 14 were 7, and 14. The maximum 18.4 f 10.9 and 19.4 * 16.2 ug/ml respectively (see Fig. 1) Postoperative levels of FDP-D also increased significantly in both groups when compared with their preoperative levels. But there were no significant differences between the hepatectomy
Vol.57, No.2
FDPAFTERHEPATECTOMY
group and the colectomy any of the postoperative
group regarding days.
postoperative
293
the
amount
of
increase
on
day
levels (mean f SD) of FPA, FIG. 1. Pre- and postoperative complex in the hepatectomy Bn 15-42, FDP, FDP-D and Pm-& -PI group (o-0) and in the colectomy group (o--O). Each normal range BO 15-42: 0.4-1.3 pmol/ml, is as follows; FPA: 0.2-0.8 pmol/ml, O-O.62 pg/ml and Pm-.&-PI complex: FDP: O-5 fig/ml, FDP-D: 0.15-0.40 yg/ml. Significance of the difference of each pre- and postoperative value between the two groups are shown by * : p
group, 3) Pmg, &-PI and Pm-AZ-PI complex : In the hepatectomy preoperative levels of Pmg decreased moderately and the postoperative levels were also decreased significantly when compared Postoperative changes of Pmg levels for with the colectomy group. both groups were similar and significant decreases were observed on days 1 and 3.
FDP AFTER HEPATECTOMY
294
Vol. 57, No. 2
levels of dp-PI in the hepatectomy Pre- and postoperative group also decreased significantly when compared with the colectomy group. The hepatectomy group did not show any significant postoperative change, on the other hand, the colectomy group showed a significant increase on day 3. Postoperative peak values of Pm-&-PI complex for both groups were observed on day 5, but the postoperative increase of Pm-X,-PI complex was not significant when compared with their preoperative levels. There were no significant differences between the groups regarding the amount of change in these values. 4) Liver function-tests : Postoperative levels of PT, Alb and T. chol were decreased significantly in the hehatectomy group on all postoperative days as compared to their preoperative levels. PT showed a significant decrease only on day 1 for the colectomy group. Alb and T. chol were not measured for the colectomy group (see Tables 3 and 4).
TABLE Pre- and and AZ,-PI, T. chol)
3
Postoperative Levels (Mean and Liver Function Tests in the Hepatectomy Group Postoperative 3rd 5th
Pre-op
1st
Fbg mg/dl (200400)
259.7 +77.0 n=30
225.0 k55.0 n=30
317.4** t85.3 n=30
285.3 k76.3 n=30
Pmg % (85-108)
79.0 t22.0 n=20
63.2* *15.8 n=20
58.9** k23.0 n=20
J2-p1
35.0 Wo"
(52-68)
35*1 ill.8 n=20
PT % (70-120)
79i15 n=30
Alb mg/dl (4.0-5.4)
chol mg/dl (125-240)
?,'
T.
(
f SD) of (PT, Alb
day 7th
Fbg, and
Pmg
14th
21th
273.2 t90.7 n=30
256.0 k83.9 n=30
213.0 k50.3 n=30
65.5 t20.7 n=20
74.0 *17.9 n=20
71.5 kl6.5 n=20
71.1 *18.8 n=20
35.9 t12.0 n=20
34.1 t13.4 n=20
33.9 k13.2 n=20
34.8 kl4.3 n=20
34.5 k7.6 n=20
57*11** n=30
58*28** n=30
6O-L29** n=30
52t30** n=30
43+32** n=30
3.69 to.35 n=30
3.53** iO.36 n=30
3.37** to.44 n=30
3.36** to.41 n=30
3.39** to.38 n=30
3.33** *0.43 n=30
3.35** *0.40 n=30
156.6 k26.3 n=30
115.8** ~26.0 n=30
118.0** *21.1 n=30
113.3** i25.6 n=30
115.8** k25.8 n=30
llO.l** *30.4 n=30
117.2** k32.8 n=30
1 : Normal Significance preoperative * : P (0.05,
40t14** n=30
ranges. of the difference was calculated between level and each postoperative level. ** : P< 0.01
Vol.57, No. 2
FDPAFTERHEPATECTOMY
TABLE Pre-
&-PI
Fbg mg/dI (200400) Pmg % (85-108)
ug/mI (52-68)
&-PI
PT % (70-120)
4.
and Postoperative Levels and PT in the Colectomy
Pre-op 353.0 *77.0 n=15
497.7** t85.2 n=15
99.6 t30.7 n=lO
60.4** il6.8 n=lO
76.0* t17.0 n=lO
55.1 i8.9 n=lO
54.0 *lo.7 n=lO
68.0** *lO.O n=lO
( ) : Normal Significance preoperative * : P
(Mean t Group.
Postoperative 3rd 5th
1st 375.4 *79.1 n=15
93*17 n=15
295
68*12** n=15
93*11 n=15
479.7* t78.6 n=15 82.6 t12.6 n=lO 62.0 t13.1 n=lO 94k18 n=15
SD)
of
Fbg,
day 7th
14th
438.4 *99.7 n=15
410.5 i103.3 n=15
95.1 t11.2 n=lO 60.9 i13.2 n=lO 88*21 n=15
Pmg,
100.5 t8.4 n=lO 59.1 t10.7 n=lO 87t16 n=15
ranges. of the difference was calculated between level and each postoperative level. ** : P(O.01
DISCUSSION The aim of the present study is to evaluate the signififibrin formation and cance of intravascular thrombin generation, its degradation in the postoperative period of hepatectomy for hepatocellular carcinoma associated with liver cirrhosis. Statistical analysis was performed on data collected through the use of recently developed laboratory assays of FPA (8), BE 15-42 (9,14), FDP-D (15), &-PI (16) and Pm-.&-PI complex (11). Data from the conventional assay of FDP (25) were also analyzed. FPA levels in blood samples have been postulated a-s an index of intravascular thrombin generation (13). Elevated FPA levels have been reported in association with several clinical disorders including postoperative period (8,13,17,19,20,21), indicating a hypercoagulable state. In the present study, FPA levels increased significantly in the early postoperative periods. Levels of BA 15-42, the earliest plasmic degradation products of fibrin, also increased immediately after the peak of FPA and then showed a gradual decline. Increase of BA 15-42 has been attributed to subsequent activation of fibrinolysis following the postoperative hypercoagulable state (22). The larger degree of operative injury of hepatectomy might be assessed by the longer operating time, the larger blood loss, and the larger amount of blood replacement as compared with those of colectomy (as illustrated in Table 1). It may be that a hypercoagulable state occurred only in the early postoperative period of hepatectomy, and that the magnitude of this state was larger for the hepatec-
296
tomy
FDP AFTER HEPATECTOMY
Vol. 57, No. 2
patients than for the colectomy patients. Circulating cross-linked fibrin derivatives are known to be specific markers of intravascular coagulation. Methods for immunological detections of X oligomers, D dimers and DD/E complexes in plasma and serum are now available (10,23). FOP-D assay used in this study reacts with D-dimers and D-monomers, but shows a fourto five-fold preference for D-dimers over D-monomers (15). FDP-D levels in plasma increased somewhat in the postoperative period of hepatectomy, but this increase was modest and not different from the increase for colectomy patients. Therefore, despite presence of a hypercoagulable state, intravascular coagulation was not apparent during this period of hepatectomy. This finding is consistent with previous reports that intravascular coagulation has not been a prominent feature among patients having various degree of liver diseases (18,24). On the other hand, FDP levels in serum did increase significantly rather late in the postoperative period for the hepatectomy patients in this study when measured by the conventional FDP assay method. This difference between measures of plasma FDP-D and serum FDP levels may be explained by the fact that the conventional FDP assay method is more reactive with the early and intermediate fragments of X and Y families than with the final fragments of D and E and also reacts with fragments of FDP derived from fibrinogenolysis and/or FDP derived from non-crosslinked fibrin (25,26). VanDeWalter et al have emphasized the significance of dysfunctional Fbg as a cause of elevated serum FDP levels in liver disease (27). In addition, early derivatives of FDP are known to be cleared from blood more slowly than are the late derivatives of FDP, and this clearing is due mostly to the reticuloendothelial system (RES) of the liver (28,29). Although we have no direct evidence of impairment of RES clearance in the present study, this function decreases among patients with liver cirrhosis markedly (28). This decrease is also proportional to the level of hepatocellular dysfunction as shown by the data of PT, Alb and T. chol in this study. Consequently it may be conceivable that serum FDP increased rather late in the postopera.tive period due not to DIC, but rather to delay in clearance of early derivatives of FDP. Furthermore this FDP may also have originated partly from defective polymerized Fbg/fibrin of dysfunctional Fbg during serum formation and/or from soluble fibrin monomer complex (4, 27). Decreased levels of &-PI have been known to cause accelerated fibrinolysis in severe diseases (16). The &-PI level in plasma is also known to increase as an acute phase reactant like but this increase is weak in response to surgical fibrinogen, trauma (30) such as was typical of the colectomy in this study. an increase of &-PI was not observed postoperatively However, probably indicating decreased synthesis in the hepatectomy group, recent reports based the analy-' in the liver. On the contrary, sis of several parameters have suggested that DIC could play an in liver cirrhosis (31,32). important role in decreasing X ,_-PI determination of Pm-&-PI complex is crucial for eValTherefore, uating fibrinolysis in severe liver diseases (11,33). Significant increase of this complex has been reported in patients with DIC (34,35). Postoperative increase of this complex in the hepatectomy group was not significant when compared with the preoperative It revealed a rather low level as compared to the coleClevels.
Vol. 57, No. 2
FDP AFTER HEPATECTOMY
297
tomy group. Whereas, S/3 15-42 increased significantly after hepatectomy. This discrepancy between the values of the two indicators may be explained by the fact that Pm generated after hepatectomy more easily binds to fibrin and release BP 15-42 rather than binding to 4 -PI and forming Pm-Jr-PI complex:As a related mechanism, fibrin formed after hepatectomy in this study is thought to contain much lower level of da-PI as compared to the level of Pmg within the fibrin network. These lowered levels may contribute to enhanced fibrinolysis. The binding of Pmg into fibrin in &-PI deficient plasma has been shown to increase through structures which are called lysine binding sites (33). Such fibrin is easily dissolved by rather small amounts of Pm and then show significant increase of B/f 15-42. Therefore, since detected levels of Pm-&-PI complex in this series of elective hepatectomy were rather low, it is suggested that plasmin action may be limited to the local fibrinolysis in response to operative fibrin generation and that no obvious systemic fibrinolysis folDIC occurs in the uncomplicated postoperative conditions. lowing
ACKNOWLEDGMENT A part of the Intractable of Japan.
this study was supported Diseases of the Ministry
by a Research Grant from of Health and Welfare
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