The Role Of Coagulation Imbalance And The Safety And Efficacy Of Anticoagulation Therapy For Splanchnic Vein Thrombosis

Background and AimSplanchnic Vein Thrombosis(SVT) is a relatively condition including portal vein thrombosis(PVT) and Budd-Chiari syndrome(BCS). SVT can cause hemodynamic disorders and induce or deteriorate portal hypertension. High mortality can be expected if variceal bleeding or ascites occurs. Unfortunately, there is no guideline or consensus for the etiology, natural history and management of SVT. Recently, great advances have been achieved about the role of procoagulation imbalance in the development of SVT. But there are few studies now and the results are conflicting. So well-designed control studies with larger samples are warrented to to clarify these issues. The hypercoagulability in liver cirrhosis justify the use of anticoagulation for cirrhotic PVT. More and more studies demonstrated that anticoagulation therapy can recanalize PVT safely and effectively, and can delay the occurrence the occurrence of hepatic decompensation. At the same time, some studies found that some patients with cirrhotic PVT can achiveve spontaneous recanalization. But most of the studies are single armed uncontrolled studies. So we designed a series of studies to investigate the role of coagulation imbalance in the development of SVT and the safety and efficacy of anticoagulation therapy for PVT in liver cirrhosis. Patients and Methods1、Studies were identified using a search strategy in the Pub Med database and the key words are: “liver cirrhosis”, “portal vein thrombosis”, “protein C”, “protein S”, and “antithrombin”. Studies were included if they met the inclusion criteria and then quality assessment of the included studies was carried out independently by 2 authors. A standardized mean difference(SMD) with 95% confidence interval(CI) was used to evaluate the effects of protein C(PC), protein S(PS) and antithrombin(AT) concentrations on PVT in liver cirrhosis. Data were pooled using fixed-effect or random-effect models. All analyses were conducted using the statistical package Rev Man version 4.2.2、Adult patients with cirrhotic PVT who were evaluated between August 2011 and June 2012 in Xijing Hospital of Digestive Diseases were prospectively screened and age-, sex- and Child-Pugh score-matched cirrhotic patients without PVT were enrolled in this study as 1:1 matched controls. In addition, between August 2011 and March 2014, all the patients referred to our hospital with a diagnosis of primary non cirrhotic PVT(NCPVT) or primary non cirrhotic BCS(NCBCS) were screened for eligibility to participate in the case-control study. We selected 100 healthy non-relatives of matched age, gender, and ethnic background as controls for NCPVT and NCBCS. We measured the plasma levels of factors II, V, VII, VIII, IX, X, XI, XII, PC, PS and AT using an automated blood coagulation analyzer. The results were expressed as percent protein activity. All data were analyzed using SPSS 16.0.3、Between January 2002 and June 2014, consecutive patients with PVT and liver cirrhosis treated at the Xijing Hospital of Digestive Diseases were analyzed retrospectively. This cohort comprises anticoagulated and non-anticoagulated groups. we used warfarin in the anticoagulation group with an initial dosage of 2.5 mg daily and were titrated carefully. The international normalization ratio(INR) was monitored every 2–3 weeks with a target level of 2–3. The Kaplan–Meier method and the log-rank test were used to determine whether there was a significant difference in decompensation and survival between the two groups. Independent predictors were assessed using a binary logistic regression model or a Cox proportional hazards model. The statistical software package SPSS 16.0 was used for the analysis. Results1、According to the inclusion and exclusion criteria, 7 studies were eligible in the meta analysis finally including 5 high high quality studies. When all the included studies were included in the meta-analysis, the pooled SMD for the effect of PC, PS and AT concentrations on PVT in liver cirrhosis using a fixed-effect or random-effect model were as follows: PC(SMD [95%CI] =- 0.23 [-0.23, 0.09], P = 0.16); PS(SMD [95%CI] =- 0.29 [-0.49,-0.08], P = 0.006); AT(SMD [95%CI] =- 0.21 [-0.56,-0.14], P = 0.24)。When only studies in which the baseline severity of liver function was similar between the 2 groups were included in the meta-analysis, the pooled SMD for the the effect of PC, PS and AT concentrations on PVT in liver cirrhosis using a fixed-effect or random-effect model were as follows: PC(SMD [95%CI] =- 0.18 [-0.62,0.25],P = 0.41);PS(SMD [95%CI] =-0.10[-0.59, 0.39],P = 0.69);AT(SMD [95%CI] =- 0.10 [-0.36, 0.16],P = 0.47)。2、When compare coagulation imbalance between cirrhotic PVT and matched cirrhotic controls, each group had 30 patients and their baseline were comparable. No difference in plasma levels of pro- and anti-coagulant factors was detected. 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(P = 0.017 and 0.005, respectively). 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. 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. Most of the ratios did not reach statistical significance in each subgroup between PVT and controls. Marginal significance was observed for ratios of factor VIII–to-PS(P=0.046), factor XII-to-PC(P=0.043) and factor XII-to PS(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, respectively) were significantly decreased in the PVT group in class B patients.When compare coagulation imbalance between NCPVT and healthy controls, factor VIII was significantly elevated(P<0.001) and factors II(P = 0.007), V(P<0.001), VII(P<0.001), IX(P = 0.035), X(P<0.001), XI(P<0.001), XII(P<0.001), PC(P<0.001), PS(P = 0.044) and AT(P<0.001) were significantly decreased in patients with NCPVT. Among all of the ratios between pro- and anti-coagulation factors in patients with NC-PVT, factor II-to-PC(P<0.001), factor VIII-to PC(P<0.001), factor IX-to-PC(P<0.001), factor VIII-to-PS(P<0.001), factor II-to-AT(P<0.001), factor VIII-to-AT(P<0.001) and factor IX-to-AT(P<0.001) were significantly increased; factor V-to-PS(P<0.001), factor VII-to-PS(P = 0.006), factor X-to-PS(P = 0.001) factor XII-to-PS(P = 0.008) and factor XII-to-PS(P = 0.001) were significantly reduced; and all other ratios did not show any difference between the two groups.When compare coagulation imbalance between NCBCS and healthy controls, factor VIII(P<0.001) was significantly elevated; factor V(P<0.001), VII(P<0.001), IX(P = 0.003), X(P<0.001), XI(P<0.001), XII(P<0.001), PC(P<0.001) and AT(P<0.001) were significantly decreased in patients with NCBCS; and no difference was observed for factor II(P = 0.088) and PS(P = 0.199) in NCBCS patients. Compared with healthy controls, the factor VIII-to-PC(P = 0.008), factor VIII-to-PS(P = 0.037) and factor VIII-to-AT(P = 0.001) ratios were significantly increased; factor V-to-PS(P = 0.006), factor VIIto-PC(P = 0.031), factor VII-to-PS(P<0.001), factor VII-to-AT(P = 0.017), factor X-to-PS(P<0.001), factor X-to-AT(P = 0.047), factor XI-to-PS(P<0.001), factor XI-to-AT(P = 0.001), factor XII-to-PS(P<0.001), and factor XII-to-AT(P = 0.031) were significantly reduced in NCBCS patients. All other ratios of pro- and anti-coagulation factors did not show any significant difference between the two groups.3、66 patients were considered to be eligible for this study including 30 patients who were anticoagulated and 36 patients who were not anticoagulated. No difference was observed for the baseline characteristics between the anticoagulation and the nonanticoagulation groups. Recanalization was assessed in 22(73.3%) anticoagulated and 16 untreated(44.4%) patients who had at least one follow-up CT during follow-up. Among anticoagulated patients, 15(68.2%) patients showed improvement, four patients(18.2%) were stable, and 3(13.6%) showed progression after a median(range) follow-up of 12.5(1.2–39.9) months. Furthermore, the portal cavernoma had disappeared in two patients after 3 and 18 months of anticoagulation. Among untreated patients, the thrombosis had improved in four patients(25%), was stable in 6(37.5%), and had progressed in 6(37.5%) after a median(range) follow-up of 11.7(1.3–68.6) months. The anticoagulation group had significantly better recanalization rates than the untreated group(P = 0.011). Only the degree of SMV [P = 0.032, hazard ratio(HR): 15.4; 95% confidence interval(CI): 1.3–200] remained a significant predictor of recanalization after univariate and multivariate analysis. In addition, no predictor of spontaneous recanalization was found in the univariate analysis in the untreated group.The probability of hepatic decompensation at 1 year was 15.6 and 17.9% in the anticoagulation group and nonanticoagulation group, respectively. No significant differences were observed in hepatic decompensation between the two groups(P = 0.847). Besides, no significant differences of death were observed between patients with and without anticoagulation(P = 0.123). Using univariate and multivariate analysis, only albumin(P = 0.06, HR: 0.860; 95% CI: 0.772–0.959) remained a significant predictor of hepatic decompensation. Anticoagulation was not a significant predictor for decompensation. When death instead of hepatic decompensation was analyzed, no predictor was found in the univariate analyses. Conclusions 1、PC, PS and AT concentrations might not be associated with the pathogenesis of PVT in liver cirrhosis, especially when the impact of liver function was excluded。 2、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. 3、For NCPVT, the elevated levels of factor VIII and the decreased levels of PC, PS and AT may play an important role in the pathogenesis. 4、For NC-BCS, the elevated levels of factor VIII and the decreased levels of PC and AT may be the most important changes of coagulation system and may play an important role in the pathogenesis. The role of PS needs further clarification. 5、Anticoagulation with warfarin might result in the resolution of more advanced PVT effectively and safely in patients with liver cirrhosis. In addition, the benefit of anticoagulation for the decompensation or death may be limited.