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Coagulation imbalance may not contribute to the development of portal vein thrombosis in patients with cirrhosis
Thrombosis Research 131 (2013) 173–177
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Regular Article
Coagulation imbalance may not contribute to the development of portal vein thrombosis in patients with cirrhosis Hui Chen a, b, Xingshun Qi a, b, Chuangye He a, Zhanxin Yin a, Daiming Fan b, Guohong Han a,⁎ a b
Department of Liver Disease and Digestive Interventional Radiology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
a r t i c l e
i n f o
Article history: Received 30 July 2012 Received in revised form 21 September 2012 Accepted 1 November 2012 Available online 14 November 2012 Keywords: Portal vein thrombosis Liver cirrhosis Coagulation protein disorders Factor VIII Protein C
a b s t r a c t Introduction: The relationship between the imbalance in pro- and anti-coagulant factors and portal vein thrombosis (PVT) in individuals with cirrhosis is unclear. The aim of this study was to determine whether the imbalance in pro- and anti-coagulant factors contributes to the development of PVT in cirrhotic patients. Materials and methods: Blood samples were collected from 30 consecutive cirrhotic patients with PVT and 30 age-, sex-, and Child-Pugh score-matched cirrhotic patients without PVT (controls), and the plasma levels of coagulation factors II, V, VII, VIII, IX, X, XI and XII and of protein C (PC), protein S (PS) and antithrombin (AT) were analyzed. The ratios of pro- vs. anti-coagulant factors were further investigated. Results: The levels of pro- and anti-coagulant factors were not statistically different between the PVT and control groups. Similar results were obtained when the patients were divided according to Child-Pugh classification. No difference was observed for the ratios of pro- vs. anti-coagulant factors between the two groups but the ratios of factor II-to-PC and factor VII-to-PC which were significantly decreased in the PVT group. Most of the ratios did not reach statistical significance in each Child-Pugh category except the followings: factor VIII-to-PS, factor XII–to-PC and factor XII-to-PS in class A patients; factor II-to-PS, factor VII-to-PC and factor VII-to-PS in class B patients. But the difference might not be so convincing. Conclusions: PVT in cirrhotic patients may not result from coagulation imbalance. © 2012 Elsevier Ltd. All rights reserved.
Introduction Coagulation is a highly integrated cellular and humoral process that is balanced by two opposing drivers [1]. The pro-coagulant driver is triggered by the complex of factor VII and its specific receptor tissue factor, which in turn activates a series of events in the coagulation cascade, ultimately leading to thrombin generation and fibrin clot formation [2]. The primary anti-coagulant drivers include proteins C (PC), its cofactor protein S (PS) and antithrombin (AT). The ratios of pro- to anti-coagulant factors can be considered indexes of the coagulation imbalance [3]. Patients with liver cirrhosis are characterized by decreased levels of most pro- and anti-coagulant factors, with the exception of factor VIII, which is markedly elevated [4–6]. For decades, it has been believed that patients with cirrhosis are prone to hypocoagulation and autoanticoagulation, and are thus protected from thrombotic episodes Abbreviations: AT, antithrombin; ETP, endogenous thrombin potential; PC, protein C; PH, portal hypertension; PS, protein S; PT, prothrombin time; PVT, portal vein thrombosis; TIPS, transjugular intrahepatic portosystemic shunt. ⁎ Corresponding author at: Department of Liver Disease and Digestive Interventional Radiology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, No. 15 West Changle Road, Xi'an, 710032, China. Tel.: +86 29 84771537; fax: +86 29 82539041. E-mail address: [email protected] (G. Han). 0049-3848/$ – see front matter © 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.thromres.2012.11.003
[7]. However, accumulating evidence from both clinical [8–11] and laboratory studies [3,12] indicates that patients with cirrhosis have an increased tendency to develop thrombosis. Thus, the prevailing paradigm has been challenged by the concept of rebalanced hemostasis in patients with liver disease [7,13]. This balance may not be as stable as in healthy individuals, and only slight alterations may tip the balance to either bleeding or thrombosis [7]. Portal vein thrombosis (PVT) is a common complication of liver cirrhosis and is associated with decreased liver function and aggravated portal hypertension [14]. The prevalence of PVT in individuals with liver cirrhosis varies from 10% to 25% [15]. It is generally accepted that decreased portal vein velocity is the primary factor underlying PVT in cirrhosis [16]. The role played by coagulation imbalance in PVT is still unclear. Tripodi et al. hypothesized that hypercoagulability due to high factor VIII combined with low PC is an additional risk factor for PVT, but this has never been demonstrated conclusively [3,17]. The aim of our study was to investigate the relationship between coagulation imbalance and PVT in patients with liver cirrhosis by comprehensively analyzing the plasma levels of pro- and anti-coagulant factors. Materials and Methods A total of 30 consecutive adult patients (19 males and 11 females; median age, 52 years) with decompensated cirrhosis and PVT who
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were evaluated between August 2011 and June 2012 were enrolled in this study. The study protocol was approved by the ethics committee of our hospital, and informed consent was obtained from all patients. Criteria for exclusion were hepatocellular carcinoma or other cancer, Budd–Chiari syndrome, splenectomy, previous shunt procedures (e.g., TIPS insertion or shunt surgery), known hemostatic disorders other than cirrhosis and blood transfusion within 3 days. No patient was receiving antiaggregants or anti-coagulants. The severity of the disease was estimated using the Child–Pugh Score [18] and the Model for End-stage Liver Disease (MELD) scoring system [19]. 30 age-, sex- and Child-Pugh score-matched cirrhotic patients without PVT also evaluated from August 2011 to June 2012 in the same center were enrolled in this study as controls.
Measurements Blood samples were taken from the antecubital vein in a standardized manner from patients who had fasted for at least 12 hours. After discarding the first 1 to 3 mL of blood, 3 mL of blood was drawn into vacuum tubes (Improve Medical, Guangzhou, China) containing 3.8% sodium citrate (ratio 9:1) as an anti-coagulant. Blood was centrifuged at 3000 g for 25 minutes at 18 °C within 30 minutes after collection. Fresh platelet-poor plasma was then harvested and all coagulation tests were performed within 4 hours after drawing the blood. All hemostasis tests were performed in an automated blood coagulation analyzer (CA-7000, Sysmex, Hyogo, Japan) using standard reagents. The activities of coagulation factors II, V, VII, VIII, IX, X, XI, and XII were determined by one-stage clotting assays using factor-deficient plasmas (Siemens, Marburg, Germany). PS activity was also measured by a clotting assay (PS Ac, Siemens, Marburg, Germany). The activities of PC and AT were measured using chromogenic assays (Berichrom PC, Berichrom AT, Siemens, Marburg, Germany). The results were expressed as percent protein activity. Normal ranges for these tests are 70–120% for factor II, V, VII, IX, X, and XI; 70–150% for factor VIII and XII; 70–140% for PC; 75–130% for protein S; and 75–125% for AT.
Definitions Cirrhosis was diagnosed based on the history of liver disease, clinical presentation such as variceal haemorrhage, ascites, spontaneous bacterial peritonitis, or hepatic encephalopathy, laboratory testing indicating decreased liver function and imaging studies which included color Doppler ultrasound, computed tomography, and MRI. Confirmation with a liver biopsy was obtained if a diagnosis of cirrhosis was inconclusive [20–22]. The decompensated stage was defined by the presence of ascites, variceal bleeding, jaundice, or encephalopathy [23]. The diagnostic criteria for PVT were imaging evidence of solid material in part or all the lumen of the portal vein trunk, portal vein branches, splenic vein or superior mesenteric vein based on color Doppler ultrasound, computed tomography, and/or angiography with a reduction or absence of portal flow.
Statistical Analysis Continuous variables were expressed as medians and ranges, and categorical variables were displayed as frequencies. Statistical analysis was performed using the appropriate parametric or nonparametric tests (t test or Wilcoxon signed ranks test for comparisons of continuous variables between paired groups, χ 2 test or Kruskal-Wallis H test for categorical data). Two-tailed p values less than 0.05 were considered significant. All data were analyzed using SPSS 16.0 (SPSS Inc., Chicago, IL).
Results The demographic characteristics of the thirty matched cirrhotic patients with and without PVT are presented in Table 1. The two groups are comparable. The diagnosis of liver cirrhosis was well-established in 57 patients by the combination of history of liver disease, clinical presentations and images and three by liver biopsy, respectively. All patients with cirrhosis were decompensated. Pro- and Anti-Coagulant Factors Between PVT and Control Groups The pro- and anti-coagulant factors are reported in Table 2. In comparison with controls, no difference in plasma levels of pro- and anti-coagulant factors was detected. Factor VIII was elevated and other pro- and anti-coagulant factors were below the lower limits of the normal ranges. Ratios of Pro- vs. Anti-Coagulant Factors Between PVT and Control Groups The ratios between pro- and anti-coagulant factors were shown in Table 3. Among these ratios, the factor II-to-PC ratio was slightly lower in the PVT group than in the paired control group (P= 0.017), as were the factor VII-to-PC ratio (P= 0.005). The ratios of factor VIII-to-PC, factor VIII-to-PS and factor VIII-to-AT were higher than other ratios in both group, but no difference was observed between the two groups (Fig. 1). Pro- vs. Anti-Coagulant Factors and Their Ratios According to Child-Pugh Classification Further, the patients were stratified according to Child-Pugh classification. The plasma levels of pro- and anti-coagulant factors were similar between the two groups in all the subgroups (Data not shown). Most of the ratios did not reach statistical significance in each subgroup between PVT and controls, including the ratios of factor VIIIto-PC (Fig. 2). Marginal significance was observed for ratios of factor VIII–to-PS (P= 0.046), factor XII-to-PC (P= 0.043) and factor XII-toPS (P= 0.046) in class A patients. The ratios of factor II-to-PS (P= 0.044), factor VII-to-PC and factor VII-to-PS (P= 0.02 and 0.022, Table 1 Demographic characteristics of 30 paired cirrhotic patients with and without PVT. Parameters
PVT
Controls
P value
Age, years Gender, male/female, n Etiology HBV, n HCV, n Alcoholic, n Other, n PH-related bleeding, n (%) Ascites, n (%) Child-Pugh score Child-Pugh class, A/B/C, n MELD score Albumin, mg/dl Bilirubin, μmol/L Creatinine, mg/dl Leukocytes, x109/L Hemoglobin, g/L Platelets, x109/L PT, s INR
52(31–76) 19/11
52(34–76) 19/11
0.583 1 0.772
19 2 1 8 22 (73.3) 24(80) 8(5–11) 7/19/4 8.86(3.25–22.03) 31.8(19–41.2) 26.8 (7.7–133.1) 82 (52–307) 2.71(0.72–29.55) 82(42–141) 45 (10–563) 15.1(12.6–18) 1.27(1.05–1.52)
20 2 1 7 26 (86.7) 24(80) 8(5–11) 7/19/4 9.33(0.36–14.28) 32.8 (22.3–47.6) 23.4(5.4–55.7) 85 (41–240) 2.94(1–17.9) 83(47–116) 57.5 (23–160) 14.5(11.9–18.4) 1.21(0.99–1.53)
0.2 1 0.102 1 0.943 0.399 0.213 0.658 0.951 0.611 0.213 0.64 0.58
NOTE. Values are expressed as median (range); n indicates number of cases. Bold values indicate P values b 0.05. HBV, hepatitis B virus; HCV, hepatitis C virus; INR, international normalized ratio; MELD, Model for End-stage Liver Disease; PH, Portal hypertension; PT, prothrombin time; PVT, portal vein thrombosis.
H. Chen et al. / Thrombosis Research 131 (2013) 173–177 Table 2 Pro- and anti-coagulant factors for 30 paired cirrhotic patients with or without PVT. Variables
PVT
Controls
P value
Factor Factor Factor Factor Factor Factor Factor Factor PC, % PS, % AT, %
55.6(34–86.6) 57.85(20–120.6) 47.5(23.1–90.9) 119(37–416.7) 59.6(40.1–163) 64.1(34.6–167.4) 41.2(16.7–83.8) 42.1(12–82) 47 (18–89) 56.5(21.6–311) 54(18.9–84.1)
56.7(35.9–78.1) 60.7(25.3–127.9) 51.7(30–108.2) 145.6(43.6–427.9) 61.8(37.5–113.5) 52.6(31.5–108.1) 40.6(18–82) 41.5(20.7–88.3) 41(10–80) 48.3(20.7–145.3) 49.5(12.8–85.4)
0.845 0.888 0.758 0.491 0.681 0.254 0.992 0.206 0.058 0.125 0.53
II, % V, % VII, % VIII, % IX, % X, % XI, % XII, %
NOTE. Values are expressed as median (range). AT, antithrombin; PC, protein C; PS, protein S; PVT, portal vein thrombosis.
respectively) were significantly decreased in the PVT group in class B patients (Table 4). Discussion This is the first study to comprehensively compare the levels of pro- and anti-coagulant factors between cirrhotic patients with and without PVT. A major strength of our present study was that the PVT patients were matched according to Child-Pugh score. Thus, the interaction of liver function was excluded. We found that the levels of pro- and anti-coagulant factors were similar between the two groups. No difference was observed for the ratios of pro- vs. anticoagulant factors between the two groups but the ratios of factor II-to-PC and factor VII-to-PC which were significantly decreased in the PVT group. Pro- and Anti-Coagulant Factors Between PVT and Control Groups Liver cirrhosis is characterized by decreased levels of most proand anti-coagulant factors with the notable exceptions of factor VIII, which are elevated [5,6,24]. In the present study, no difference was
Table 3 Ratios of pro- to anti-coagulant factors in 30 paired cirrhotic patients with and without PVT. Ratios Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor
II /PC II /PS II /AT V /PC V /PS V /AT VII /PC VII /PS VII /AT VIII /PC VIII /PS VIII /AT IX /PC IX /PS IX /AT X /PC X /PS X /AT XI /PC XI /PS XI /AT XII /PC XII /PS XII /AT
PVT
Controls
P value
1.2 (0.79–1.93) 1.04(0.21–2.25) 1.03(0.82–3.1) 1.14(0.5–3.81) 0.91(0.2–3.01) 1.1(0.32–5.07) 1.02(0.59–1.99) 0.87(0.13–2.61) 1(0.43–2.7) 2.65(0.92–10.84) 2.53(0.35–6.78) 2.3(0.68–12.44) 1.3(0.77–2.79) 1.13(0.13–2.76) 1.2(0.71–4.99) 1.41(0.71–2.97) 1.1(0.21–3.24) 1.3 (0.61–3.67) 0.85(0.44–2.14) 0.72(0.11–1.81) 0.87(0.31–1.97) 0.92(0.22–2.78) 0.75(0.12–1.81) 0.74(0.21–3.51)
1.27(0.87–3.81) 1.1(0.29–3.39) 1.18(0.7–2.83) 1.43(0.65–3.61) 1.21(0.4–3.14) 1.29(0.49–4.76) 1.2 (0.73–4.16) 1.06(0.35–3.07) 1.1 (0.62–3.09) 3.37(1.06–16.85) 2.75(0.71–10.23) 3.1(1.23–10.07) 1.47(0.79–4.57) 1.16(0.26–3.55) 1.48(0.76–3.39) 1.4(0.68–4.51) 1.15(0.33–3.86) 1.07(0.49–3.79) 0.9(0.5–2.81) 0.72(0.17–2.64) 0.81(0.34–3.56) 0.98(0.33–2.79) 0.94(0.36–2.6) 0.87(0.48–4.37)
0.017 0.177 0.405 0.271 0.17 0.382 0.005 0.103 0.147 0.213 0.265 0.199 0.221 0.345 0.405 0.926 0.721 0.975 0.237 0.43 0.75 0.09 0.068 0.239
NOTE. Values are expressed as median (range); Bold values indicate P values b 0.05. AT, antithrombin; PC, protein C; PS, protein S; PVT, portal vein thrombosis.
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observed for the pro- and anti-coagulant factors between the two groups. Similar results were obtained in each Child-Pugh category. Studies comparing pro-coagulant factors between the two groups were scarce. Fimognari et al. compared factor VIII levels between cirrhotic patients with and without asymptomatic PVT [25]. No difference of the levels of factor VIII was observed between the two groups [25]. Amitrano et al. found median plasma levels of factor II, VII, X, V were similar between cirrhotic patients with and without PVT [26]. In agreement with these studies, we also demonstrated that the concentrations of all the pro-coagulant factors measured were similar between the two groups. Besides, three studies demonstrated that the levels of PC, PS and AT in cirrhotic patients with and without PVT were similar [26–28]. In contrast, Zocco et al. found that serum levels of PC and PS were lower in cirrhotic patients who developed PVT during the follow-up period than in those without PVT [16]. Zhang et al. also found that plasma PC and PS levels were significantly decreased in the PVT group than those in the control group [29]. The differences among these studies may result from study design and the population selection. Recently, our meta-analysis of these previous studies revealed that PC, PS and AT concentrations were not significantly different between cirrhotic patients with and without PVT [30], which is in accordance with the present finding. The Ratios of Pro- vs. Anti-Coagulant Factors Between PVT and Control Groups The ratios of pro- to anti-coagulant factors can be considered indexes of the coagulation imbalance. No difference was observed for the ratios of pro- to anti-coagulant factors but the ratios of factor II-to-PC and factor VII-to-PC. Some ratios in Child-Pugh class A showed marginal significance which might not be so convincing given the limited cases. Although some ratios in class B patients showed statistical significance, all the levels of pro- and anti-coagulant factors were similar between the two groups. This paradox may indicate that there was little difference for the ratios between PVT and controls. Tripodi et al. demonstrated a state of hypercoagulability in plasma from patients with cirrhosis and inferred that this hypercoagulability was due to increased levels of factor VIII and decreased levels of PC [3]. Furthermore, these authors hypothesized that hypercoagulability due to high factor VIII combined with low PC is an additional risk factor for the development of PVT [17]. This hypothesis is attractive, but it was not confirmed by our study in which the ratios of factor VIII-to-PC were similar in the PVT and control groups. Therefore the development of PVT in individuals with decompensated cirrhosis appears not to result from an imbalance in the factor VIII-to-PC ratio. Limitations Endogenous thrombin potential (ETP) represents the balance between the actions of pro- and anti-coagulants in plasma and is more reliable for coagulation imbalance [31]. However, this method was not available in our hospital. The present study has the potential limitation that the in vitro ratios of pro- and anti-coagulant factors are not truly representative of their expression in vivo, but their changes can roughly reflect the imbalance of coagulation. Another limitation was the relatively small number of samples due to the relatively low prevalence of PVT in liver cirrhosis and rigorous exclusion criteria which reduce the interactions between coagulation parameters and confounding factors. Besides, the uneven distribution of Child-Pugh classification may be compensated for the rigorously match. Finally, because it is difficult to discriminate between congenital and acquired deficiencies owing to impaired liver function, thrombophilic work-up was not performed in PVT cirrhotic patients.
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Fig. 1. Box plots for the ratios of factor VIII-to-PC, factor VIII-to-AT, and factor VIII-to-PS between 30 paired cirrhotic patients with and without PVT (controls).
Fig. 2. Box plots for the comparison of factor VIII-to-PC, factor VIII-to-AT, and factor VIII-to-PS ratios in 19 Child-Pugh class B patients with and without PVT (controls).
In conclusion, the hypothesis that the hypercoagulability of plasma in patients with cirrhosis is caused by an imbalance of factor VIII and PC may not be supported by the current evidence. Coagulation imbalance may not play a role in the formation of PVT. Further prospective studies with larger samples are warranted to test this new hypothesis.
Acknowledgments
Conflict of Interest Statement
References
No potential conflicts of interest exist.
Table 4 Ratios of pro- to anti-coagulant factors for 19 paired Child-Pugh B cirrhotic patients with or without PVT. Ratios Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor
II /PC II /PS II /AT V /PC V /PS V /AT VII /PC VII /PS VII /AT VIII /PC VIII /PS VIII /AT IX /PC IX /PS IX /AT X /PC X /PS X /AT XI /PC XI /PS XI /AT XII /PC XII /PS XII /AT
PVT
Controls
P value
1.26(0.89–1.93) 0.98(0.21–1.66) 1.08(0.82–3.1) 1.19(0.5–3.81) 0.9(0.2–1.99) 1.32(0.32–5.07) 0.99(0.66–1.88) 0.72(0.13–1.34) 0.86(0.43–2.7) 3.15(0.97–10.84) 2.5(0.35–4.19) 2.6(0.68–12.44) 1.3(0.79–2.79) 1.08(0.13–1.99) 1.17(0.71–4.99) 1.45(0.82–2.97) 1.1(0.21–2.29) 1.3(0.64–3.67) 0.83(0.44–2.14) 0.63(0.11–1.47) 0.8(0.31–1.97) 0.95(0.56–2.78) 0.74(0.12–1.47) 0.85(0.47–3.51)
1.3(0.93–2.47) 1.09(0.43–3.39) 1.18(0.9–2.16) 1.4(0.65–2.69) 1.16(0.4–3.14) 1.19(0.49–3.41) 1.33(0.73–1.6) 1.05(0.44–3.07) 1 (0.62–2.03) 3.33(1.06–16.85) 3.08(1.14–10.23) 3.18(1.51–10.07) 1.56(0.97–2.57) 1.2(0.46–3.55) 1.53(0.81–2.72) 1.4(0.68–3.14) 0.97(0.48–3.86) 1.1(0.7–3.79) 0.83(0.5–2.81) 0.73(0.37–2.64) 0.8 (0.34–3.56) 0.98(0.53–2.71) 0.96(0.37–2.6) 0.9(0.48–4.37)
0.07 0.044 0.658 0.629 0.295 0.936 0.02 0.022 0.376 0.398 0.184 0.355 0.494 0.117 0.658 0.748 0.355 0.717 0.629 0.198 0.904 0.52 0.117 0.398
NOTE. Values are expressed as median (range); Bold values indicate values under P values b0.05. AT, antithrombin; PC, protein C; PS, protein S; PVT, portal vein thrombosis.
This study was supported by grants from the National Natural Science Foundation of China (No. 81000864). The authors gratefully acknowledge the cooperation of Jing Niu, Ziwei Liu and Feifei Wu in data collection.
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Coagulation imbalance may not contribute to the development of portal vein thrombosis in patients with cirrhosis Hui Chen a, b, Xingshun Qi a, b, Chuangye He a, Zhanxin Yin a, Daiming Fan b, Guohong Han a,⁎ a b
Department of Liver Disease and Digestive Interventional Radiology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
a r t i c l e
i n f o
Article history: Received 30 July 2012 Received in revised form 21 September 2012 Accepted 1 November 2012 Available online 14 November 2012 Keywords: Portal vein thrombosis Liver cirrhosis Coagulation protein disorders Factor VIII Protein C
a b s t r a c t Introduction: The relationship between the imbalance in pro- and anti-coagulant factors and portal vein thrombosis (PVT) in individuals with cirrhosis is unclear. The aim of this study was to determine whether the imbalance in pro- and anti-coagulant factors contributes to the development of PVT in cirrhotic patients. Materials and methods: Blood samples were collected from 30 consecutive cirrhotic patients with PVT and 30 age-, sex-, and Child-Pugh score-matched cirrhotic patients without PVT (controls), and the plasma levels of coagulation factors II, V, VII, VIII, IX, X, XI and XII and of protein C (PC), protein S (PS) and antithrombin (AT) were analyzed. The ratios of pro- vs. anti-coagulant factors were further investigated. Results: The levels of pro- and anti-coagulant factors were not statistically different between the PVT and control groups. Similar results were obtained when the patients were divided according to Child-Pugh classification. No difference was observed for the ratios of pro- vs. anti-coagulant factors between the two groups but the ratios of factor II-to-PC and factor VII-to-PC which were significantly decreased in the PVT group. Most of the ratios did not reach statistical significance in each Child-Pugh category except the followings: factor VIII-to-PS, factor XII–to-PC and factor XII-to-PS in class A patients; factor II-to-PS, factor VII-to-PC and factor VII-to-PS in class B patients. But the difference might not be so convincing. Conclusions: PVT in cirrhotic patients may not result from coagulation imbalance. © 2012 Elsevier Ltd. All rights reserved.
Introduction Coagulation is a highly integrated cellular and humoral process that is balanced by two opposing drivers [1]. The pro-coagulant driver is triggered by the complex of factor VII and its specific receptor tissue factor, which in turn activates a series of events in the coagulation cascade, ultimately leading to thrombin generation and fibrin clot formation [2]. The primary anti-coagulant drivers include proteins C (PC), its cofactor protein S (PS) and antithrombin (AT). The ratios of pro- to anti-coagulant factors can be considered indexes of the coagulation imbalance [3]. Patients with liver cirrhosis are characterized by decreased levels of most pro- and anti-coagulant factors, with the exception of factor VIII, which is markedly elevated [4–6]. For decades, it has been believed that patients with cirrhosis are prone to hypocoagulation and autoanticoagulation, and are thus protected from thrombotic episodes Abbreviations: AT, antithrombin; ETP, endogenous thrombin potential; PC, protein C; PH, portal hypertension; PS, protein S; PT, prothrombin time; PVT, portal vein thrombosis; TIPS, transjugular intrahepatic portosystemic shunt. ⁎ Corresponding author at: Department of Liver Disease and Digestive Interventional Radiology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, No. 15 West Changle Road, Xi'an, 710032, China. Tel.: +86 29 84771537; fax: +86 29 82539041. E-mail address: [email protected] (G. Han). 0049-3848/$ – see front matter © 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.thromres.2012.11.003
[7]. However, accumulating evidence from both clinical [8–11] and laboratory studies [3,12] indicates that patients with cirrhosis have an increased tendency to develop thrombosis. Thus, the prevailing paradigm has been challenged by the concept of rebalanced hemostasis in patients with liver disease [7,13]. This balance may not be as stable as in healthy individuals, and only slight alterations may tip the balance to either bleeding or thrombosis [7]. Portal vein thrombosis (PVT) is a common complication of liver cirrhosis and is associated with decreased liver function and aggravated portal hypertension [14]. The prevalence of PVT in individuals with liver cirrhosis varies from 10% to 25% [15]. It is generally accepted that decreased portal vein velocity is the primary factor underlying PVT in cirrhosis [16]. The role played by coagulation imbalance in PVT is still unclear. Tripodi et al. hypothesized that hypercoagulability due to high factor VIII combined with low PC is an additional risk factor for PVT, but this has never been demonstrated conclusively [3,17]. The aim of our study was to investigate the relationship between coagulation imbalance and PVT in patients with liver cirrhosis by comprehensively analyzing the plasma levels of pro- and anti-coagulant factors. Materials and Methods A total of 30 consecutive adult patients (19 males and 11 females; median age, 52 years) with decompensated cirrhosis and PVT who
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were evaluated between August 2011 and June 2012 were enrolled in this study. The study protocol was approved by the ethics committee of our hospital, and informed consent was obtained from all patients. Criteria for exclusion were hepatocellular carcinoma or other cancer, Budd–Chiari syndrome, splenectomy, previous shunt procedures (e.g., TIPS insertion or shunt surgery), known hemostatic disorders other than cirrhosis and blood transfusion within 3 days. No patient was receiving antiaggregants or anti-coagulants. The severity of the disease was estimated using the Child–Pugh Score [18] and the Model for End-stage Liver Disease (MELD) scoring system [19]. 30 age-, sex- and Child-Pugh score-matched cirrhotic patients without PVT also evaluated from August 2011 to June 2012 in the same center were enrolled in this study as controls.
Measurements Blood samples were taken from the antecubital vein in a standardized manner from patients who had fasted for at least 12 hours. After discarding the first 1 to 3 mL of blood, 3 mL of blood was drawn into vacuum tubes (Improve Medical, Guangzhou, China) containing 3.8% sodium citrate (ratio 9:1) as an anti-coagulant. Blood was centrifuged at 3000 g for 25 minutes at 18 °C within 30 minutes after collection. Fresh platelet-poor plasma was then harvested and all coagulation tests were performed within 4 hours after drawing the blood. All hemostasis tests were performed in an automated blood coagulation analyzer (CA-7000, Sysmex, Hyogo, Japan) using standard reagents. The activities of coagulation factors II, V, VII, VIII, IX, X, XI, and XII were determined by one-stage clotting assays using factor-deficient plasmas (Siemens, Marburg, Germany). PS activity was also measured by a clotting assay (PS Ac, Siemens, Marburg, Germany). The activities of PC and AT were measured using chromogenic assays (Berichrom PC, Berichrom AT, Siemens, Marburg, Germany). The results were expressed as percent protein activity. Normal ranges for these tests are 70–120% for factor II, V, VII, IX, X, and XI; 70–150% for factor VIII and XII; 70–140% for PC; 75–130% for protein S; and 75–125% for AT.
Definitions Cirrhosis was diagnosed based on the history of liver disease, clinical presentation such as variceal haemorrhage, ascites, spontaneous bacterial peritonitis, or hepatic encephalopathy, laboratory testing indicating decreased liver function and imaging studies which included color Doppler ultrasound, computed tomography, and MRI. Confirmation with a liver biopsy was obtained if a diagnosis of cirrhosis was inconclusive [20–22]. The decompensated stage was defined by the presence of ascites, variceal bleeding, jaundice, or encephalopathy [23]. The diagnostic criteria for PVT were imaging evidence of solid material in part or all the lumen of the portal vein trunk, portal vein branches, splenic vein or superior mesenteric vein based on color Doppler ultrasound, computed tomography, and/or angiography with a reduction or absence of portal flow.
Statistical Analysis Continuous variables were expressed as medians and ranges, and categorical variables were displayed as frequencies. Statistical analysis was performed using the appropriate parametric or nonparametric tests (t test or Wilcoxon signed ranks test for comparisons of continuous variables between paired groups, χ 2 test or Kruskal-Wallis H test for categorical data). Two-tailed p values less than 0.05 were considered significant. All data were analyzed using SPSS 16.0 (SPSS Inc., Chicago, IL).
Results The demographic characteristics of the thirty matched cirrhotic patients with and without PVT are presented in Table 1. The two groups are comparable. The diagnosis of liver cirrhosis was well-established in 57 patients by the combination of history of liver disease, clinical presentations and images and three by liver biopsy, respectively. All patients with cirrhosis were decompensated. Pro- and Anti-Coagulant Factors Between PVT and Control Groups The pro- and anti-coagulant factors are reported in Table 2. In comparison with controls, no difference in plasma levels of pro- and anti-coagulant factors was detected. Factor VIII was elevated and other pro- and anti-coagulant factors were below the lower limits of the normal ranges. Ratios of Pro- vs. Anti-Coagulant Factors Between PVT and Control Groups The ratios between pro- and anti-coagulant factors were shown in Table 3. Among these ratios, the factor II-to-PC ratio was slightly lower in the PVT group than in the paired control group (P= 0.017), as were the factor VII-to-PC ratio (P= 0.005). The ratios of factor VIII-to-PC, factor VIII-to-PS and factor VIII-to-AT were higher than other ratios in both group, but no difference was observed between the two groups (Fig. 1). Pro- vs. Anti-Coagulant Factors and Their Ratios According to Child-Pugh Classification Further, the patients were stratified according to Child-Pugh classification. The plasma levels of pro- and anti-coagulant factors were similar between the two groups in all the subgroups (Data not shown). Most of the ratios did not reach statistical significance in each subgroup between PVT and controls, including the ratios of factor VIIIto-PC (Fig. 2). Marginal significance was observed for ratios of factor VIII–to-PS (P= 0.046), factor XII-to-PC (P= 0.043) and factor XII-toPS (P= 0.046) in class A patients. The ratios of factor II-to-PS (P= 0.044), factor VII-to-PC and factor VII-to-PS (P= 0.02 and 0.022, Table 1 Demographic characteristics of 30 paired cirrhotic patients with and without PVT. Parameters
PVT
Controls
P value
Age, years Gender, male/female, n Etiology HBV, n HCV, n Alcoholic, n Other, n PH-related bleeding, n (%) Ascites, n (%) Child-Pugh score Child-Pugh class, A/B/C, n MELD score Albumin, mg/dl Bilirubin, μmol/L Creatinine, mg/dl Leukocytes, x109/L Hemoglobin, g/L Platelets, x109/L PT, s INR
52(31–76) 19/11
52(34–76) 19/11
0.583 1 0.772
19 2 1 8 22 (73.3) 24(80) 8(5–11) 7/19/4 8.86(3.25–22.03) 31.8(19–41.2) 26.8 (7.7–133.1) 82 (52–307) 2.71(0.72–29.55) 82(42–141) 45 (10–563) 15.1(12.6–18) 1.27(1.05–1.52)
20 2 1 7 26 (86.7) 24(80) 8(5–11) 7/19/4 9.33(0.36–14.28) 32.8 (22.3–47.6) 23.4(5.4–55.7) 85 (41–240) 2.94(1–17.9) 83(47–116) 57.5 (23–160) 14.5(11.9–18.4) 1.21(0.99–1.53)
0.2 1 0.102 1 0.943 0.399 0.213 0.658 0.951 0.611 0.213 0.64 0.58
NOTE. Values are expressed as median (range); n indicates number of cases. Bold values indicate P values b 0.05. HBV, hepatitis B virus; HCV, hepatitis C virus; INR, international normalized ratio; MELD, Model for End-stage Liver Disease; PH, Portal hypertension; PT, prothrombin time; PVT, portal vein thrombosis.
H. Chen et al. / Thrombosis Research 131 (2013) 173–177 Table 2 Pro- and anti-coagulant factors for 30 paired cirrhotic patients with or without PVT. Variables
PVT
Controls
P value
Factor Factor Factor Factor Factor Factor Factor Factor PC, % PS, % AT, %
55.6(34–86.6) 57.85(20–120.6) 47.5(23.1–90.9) 119(37–416.7) 59.6(40.1–163) 64.1(34.6–167.4) 41.2(16.7–83.8) 42.1(12–82) 47 (18–89) 56.5(21.6–311) 54(18.9–84.1)
56.7(35.9–78.1) 60.7(25.3–127.9) 51.7(30–108.2) 145.6(43.6–427.9) 61.8(37.5–113.5) 52.6(31.5–108.1) 40.6(18–82) 41.5(20.7–88.3) 41(10–80) 48.3(20.7–145.3) 49.5(12.8–85.4)
0.845 0.888 0.758 0.491 0.681 0.254 0.992 0.206 0.058 0.125 0.53
II, % V, % VII, % VIII, % IX, % X, % XI, % XII, %
NOTE. Values are expressed as median (range). AT, antithrombin; PC, protein C; PS, protein S; PVT, portal vein thrombosis.
respectively) were significantly decreased in the PVT group in class B patients (Table 4). Discussion This is the first study to comprehensively compare the levels of pro- and anti-coagulant factors between cirrhotic patients with and without PVT. A major strength of our present study was that the PVT patients were matched according to Child-Pugh score. Thus, the interaction of liver function was excluded. We found that the levels of pro- and anti-coagulant factors were similar between the two groups. No difference was observed for the ratios of pro- vs. anticoagulant factors between the two groups but the ratios of factor II-to-PC and factor VII-to-PC which were significantly decreased in the PVT group. Pro- and Anti-Coagulant Factors Between PVT and Control Groups Liver cirrhosis is characterized by decreased levels of most proand anti-coagulant factors with the notable exceptions of factor VIII, which are elevated [5,6,24]. In the present study, no difference was
Table 3 Ratios of pro- to anti-coagulant factors in 30 paired cirrhotic patients with and without PVT. Ratios Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor
II /PC II /PS II /AT V /PC V /PS V /AT VII /PC VII /PS VII /AT VIII /PC VIII /PS VIII /AT IX /PC IX /PS IX /AT X /PC X /PS X /AT XI /PC XI /PS XI /AT XII /PC XII /PS XII /AT
PVT
Controls
P value
1.2 (0.79–1.93) 1.04(0.21–2.25) 1.03(0.82–3.1) 1.14(0.5–3.81) 0.91(0.2–3.01) 1.1(0.32–5.07) 1.02(0.59–1.99) 0.87(0.13–2.61) 1(0.43–2.7) 2.65(0.92–10.84) 2.53(0.35–6.78) 2.3(0.68–12.44) 1.3(0.77–2.79) 1.13(0.13–2.76) 1.2(0.71–4.99) 1.41(0.71–2.97) 1.1(0.21–3.24) 1.3 (0.61–3.67) 0.85(0.44–2.14) 0.72(0.11–1.81) 0.87(0.31–1.97) 0.92(0.22–2.78) 0.75(0.12–1.81) 0.74(0.21–3.51)
1.27(0.87–3.81) 1.1(0.29–3.39) 1.18(0.7–2.83) 1.43(0.65–3.61) 1.21(0.4–3.14) 1.29(0.49–4.76) 1.2 (0.73–4.16) 1.06(0.35–3.07) 1.1 (0.62–3.09) 3.37(1.06–16.85) 2.75(0.71–10.23) 3.1(1.23–10.07) 1.47(0.79–4.57) 1.16(0.26–3.55) 1.48(0.76–3.39) 1.4(0.68–4.51) 1.15(0.33–3.86) 1.07(0.49–3.79) 0.9(0.5–2.81) 0.72(0.17–2.64) 0.81(0.34–3.56) 0.98(0.33–2.79) 0.94(0.36–2.6) 0.87(0.48–4.37)
0.017 0.177 0.405 0.271 0.17 0.382 0.005 0.103 0.147 0.213 0.265 0.199 0.221 0.345 0.405 0.926 0.721 0.975 0.237 0.43 0.75 0.09 0.068 0.239
NOTE. Values are expressed as median (range); Bold values indicate P values b 0.05. AT, antithrombin; PC, protein C; PS, protein S; PVT, portal vein thrombosis.
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observed for the pro- and anti-coagulant factors between the two groups. Similar results were obtained in each Child-Pugh category. Studies comparing pro-coagulant factors between the two groups were scarce. Fimognari et al. compared factor VIII levels between cirrhotic patients with and without asymptomatic PVT [25]. No difference of the levels of factor VIII was observed between the two groups [25]. Amitrano et al. found median plasma levels of factor II, VII, X, V were similar between cirrhotic patients with and without PVT [26]. In agreement with these studies, we also demonstrated that the concentrations of all the pro-coagulant factors measured were similar between the two groups. Besides, three studies demonstrated that the levels of PC, PS and AT in cirrhotic patients with and without PVT were similar [26–28]. In contrast, Zocco et al. found that serum levels of PC and PS were lower in cirrhotic patients who developed PVT during the follow-up period than in those without PVT [16]. Zhang et al. also found that plasma PC and PS levels were significantly decreased in the PVT group than those in the control group [29]. The differences among these studies may result from study design and the population selection. Recently, our meta-analysis of these previous studies revealed that PC, PS and AT concentrations were not significantly different between cirrhotic patients with and without PVT [30], which is in accordance with the present finding. The Ratios of Pro- vs. Anti-Coagulant Factors Between PVT and Control Groups The ratios of pro- to anti-coagulant factors can be considered indexes of the coagulation imbalance. No difference was observed for the ratios of pro- to anti-coagulant factors but the ratios of factor II-to-PC and factor VII-to-PC. Some ratios in Child-Pugh class A showed marginal significance which might not be so convincing given the limited cases. Although some ratios in class B patients showed statistical significance, all the levels of pro- and anti-coagulant factors were similar between the two groups. This paradox may indicate that there was little difference for the ratios between PVT and controls. Tripodi et al. demonstrated a state of hypercoagulability in plasma from patients with cirrhosis and inferred that this hypercoagulability was due to increased levels of factor VIII and decreased levels of PC [3]. Furthermore, these authors hypothesized that hypercoagulability due to high factor VIII combined with low PC is an additional risk factor for the development of PVT [17]. This hypothesis is attractive, but it was not confirmed by our study in which the ratios of factor VIII-to-PC were similar in the PVT and control groups. Therefore the development of PVT in individuals with decompensated cirrhosis appears not to result from an imbalance in the factor VIII-to-PC ratio. Limitations Endogenous thrombin potential (ETP) represents the balance between the actions of pro- and anti-coagulants in plasma and is more reliable for coagulation imbalance [31]. However, this method was not available in our hospital. The present study has the potential limitation that the in vitro ratios of pro- and anti-coagulant factors are not truly representative of their expression in vivo, but their changes can roughly reflect the imbalance of coagulation. Another limitation was the relatively small number of samples due to the relatively low prevalence of PVT in liver cirrhosis and rigorous exclusion criteria which reduce the interactions between coagulation parameters and confounding factors. Besides, the uneven distribution of Child-Pugh classification may be compensated for the rigorously match. Finally, because it is difficult to discriminate between congenital and acquired deficiencies owing to impaired liver function, thrombophilic work-up was not performed in PVT cirrhotic patients.
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Fig. 1. Box plots for the ratios of factor VIII-to-PC, factor VIII-to-AT, and factor VIII-to-PS between 30 paired cirrhotic patients with and without PVT (controls).
Fig. 2. Box plots for the comparison of factor VIII-to-PC, factor VIII-to-AT, and factor VIII-to-PS ratios in 19 Child-Pugh class B patients with and without PVT (controls).
In conclusion, the hypothesis that the hypercoagulability of plasma in patients with cirrhosis is caused by an imbalance of factor VIII and PC may not be supported by the current evidence. Coagulation imbalance may not play a role in the formation of PVT. Further prospective studies with larger samples are warranted to test this new hypothesis.
Acknowledgments
Conflict of Interest Statement
References
No potential conflicts of interest exist.
Table 4 Ratios of pro- to anti-coagulant factors for 19 paired Child-Pugh B cirrhotic patients with or without PVT. Ratios Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor Factor
II /PC II /PS II /AT V /PC V /PS V /AT VII /PC VII /PS VII /AT VIII /PC VIII /PS VIII /AT IX /PC IX /PS IX /AT X /PC X /PS X /AT XI /PC XI /PS XI /AT XII /PC XII /PS XII /AT
PVT
Controls
P value
1.26(0.89–1.93) 0.98(0.21–1.66) 1.08(0.82–3.1) 1.19(0.5–3.81) 0.9(0.2–1.99) 1.32(0.32–5.07) 0.99(0.66–1.88) 0.72(0.13–1.34) 0.86(0.43–2.7) 3.15(0.97–10.84) 2.5(0.35–4.19) 2.6(0.68–12.44) 1.3(0.79–2.79) 1.08(0.13–1.99) 1.17(0.71–4.99) 1.45(0.82–2.97) 1.1(0.21–2.29) 1.3(0.64–3.67) 0.83(0.44–2.14) 0.63(0.11–1.47) 0.8(0.31–1.97) 0.95(0.56–2.78) 0.74(0.12–1.47) 0.85(0.47–3.51)
1.3(0.93–2.47) 1.09(0.43–3.39) 1.18(0.9–2.16) 1.4(0.65–2.69) 1.16(0.4–3.14) 1.19(0.49–3.41) 1.33(0.73–1.6) 1.05(0.44–3.07) 1 (0.62–2.03) 3.33(1.06–16.85) 3.08(1.14–10.23) 3.18(1.51–10.07) 1.56(0.97–2.57) 1.2(0.46–3.55) 1.53(0.81–2.72) 1.4(0.68–3.14) 0.97(0.48–3.86) 1.1(0.7–3.79) 0.83(0.5–2.81) 0.73(0.37–2.64) 0.8 (0.34–3.56) 0.98(0.53–2.71) 0.96(0.37–2.6) 0.9(0.48–4.37)
0.07 0.044 0.658 0.629 0.295 0.936 0.02 0.022 0.376 0.398 0.184 0.355 0.494 0.117 0.658 0.748 0.355 0.717 0.629 0.198 0.904 0.52 0.117 0.398
NOTE. Values are expressed as median (range); Bold values indicate values under P values b0.05. AT, antithrombin; PC, protein C; PS, protein S; PVT, portal vein thrombosis.
This study was supported by grants from the National Natural Science Foundation of China (No. 81000864). The authors gratefully acknowledge the cooperation of Jing Niu, Ziwei Liu and Feifei Wu in data collection.
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