| Research backgroundPortal vein thrombosis(PVT)refers to the occurrence of thrombus in the main portal vein and the left and right branches of the portal vein,with or without mesenteric vein and splenic vein thrombosis.The prevalence of PVT in cirrhosis is 10%-25%,which may increase the risk of upper gastrointestinal bleeding,ascites,acute kidney injury,long-term death,and death after liver transplantation in patients with cirrhosis.The 2019 edition of the guidelines for the diagnosis and treatment of liver cirrhosis pointed out that the earlier the anticoagulant treatment of PVT in liver cirrhosis,the higher the portal vein recanalization rate.The recanalization rate was 69%when the treatment was started in the first week,while it decreased by 25%when the treatment was started in the second week.However,in the clinic,PVT in cirrhosis is often found in routine imaging examinations,which is difficult to find in early cirrhosis,thus missing the best treatment time.In addition,the latest research shows that the components of PVT in liver cirrhosis are different from other venous thrombi.The main components of PVT are portal vein intimal thickening and fibrosis,and only 1/3 patients are accompanied by fibrin-rich thrombi.Anticoagulant drugs only have a good curative effect on newly formed PVT rich in fibrin thrombus but have limited effect on thickened vascular intima and fibrous tissue,as well as chronic PVT recanalization.The commonly used anticoagulant drugs include low molecular weight heparin,rivaroxaban,and warfarin.The choice of anticoagulant drugs for PVT in liver cirrhosis is still inconclusive.Therefore,this study focused on the research status at home and abroad,closely followed the core mechanism of the pathogenesis of PVT in liver cirrhosis and the bottleneck of anticoagulation treatment,and carried out retrospective and animal experimental research.Part I retrospective investigation of diagnosis and treatment of portal vein thrombosis in liver cirrhosisObjective The aim of this study was to understand the basic situation of cirrhotic patients with portal vein thrombosis,and analyze the influencing factors of cirrhotic patients with portal vein thrombosis and thrombosis outcome,to provide a scientific basis for clinical research and clinical diagnosis and treatment of cirrhotic patients with portal vein thrombosis.MethodsIn this study,convenient sampling was used to include patients with portal vein thrombosis in Qilu Hospital of Shandong University,the second hospital of Shandong University,the Affiliated Hospital of Shandong University of traditional Chinese medicine,and Qianfo Mountain hospital of Shandong Province.The basic information,clinical data,laboratory data,and diagnosis and treatment data of patients were collected from the hospital system and medical record system and were retrospectively sorted and analyzed to reveal the clinical characteristics and formation-related factors of portal vein thrombosis in cirrhosis,Evaluate the efficacy of anticoagulant drugs.Results1.Basic information about the research object:A total of 266 patients with cirrhosis and portal vein thrombosis were included in this study,including 160 males and 106 females.The youngest was 24 years old and the oldest was 84 years old.There were 198 cases of viral hepatitis in 266 patients,including 155 cases of viral cirrhosis B,7 cases of viral cirrhosis C,and 36 cases of alcoholic cirrhosis.There were 20 cases of autoimmune cirrhosis and 48 cases of others.Among the 266 patients,204 patients(76.7%)had decompensated liver cirrhosis.103 cases(50.1%)were complicated with upper gastrointestinal bleeding,156 cases(76.5%)with ascites,55 cases(27%)with both;40 cases were accompanied by abnormal glucose metabolism,accounting for 15%;29 cases(10.9%)were accompanied by renal function injury,including 12 cases with elevated creatinine and 17 cases with elevated cystatin C,and 2 cases with elevated creatinine and cystatin C;Platelets ≤50 × 109/L in 67 cases,accounting for 25.2%;152 cases(57.14%)had elevated D-dimer.A total of 195 of 266 patients underwent surgery.Among 195 surgical patients,131 cases developed PVT after the operation,including 23 cases after endoscopic ligation/sclerotherapy,42 cases after splenectomy,11 cases after splenic embolization,33 cases after endoscopic splenectomy,and 22 cases after endoscopic splenectomy and splenic embolization.A total of 52 patients were treated with anticoagulant drugs in 266 patients.The results of thrombus recanalization in cirrhotic patients with portal vein thrombosis using anticoagulant drugs showed that the highest rate of warfarin application was 33.3%,followed by low molecular weight heparin and warfarin continuation(26.7%),low molecular weight heparin thrombus recanalization rate(19%),low molecular weight heparin and rivaroxaban continuation(12.5%),rivaroxaban recanalization rate ratio was the lowest of 3.8%.2.Analysis of influencing factors of portal vein thrombosis in liver cirrhosis2.1 The analysis of PVT time in patients with liver cirrhosis and portal vein thrombosis after surgery showed that 195 of 266 patients received endoscopic and surgical treatment,and 131 patients had PVT after surgery.Of 131 patients with liver cirrhosis and portal vein thrombosis after operation,51(38.9%)had thrombosis within 6 months after operation;Among them,37 cases(35.9%)occurred within 6 months after splenectomy/splenic embolization;There were 29 cases(45.3%)within 6 months after endoscopic ligation/sclerotherapy.2.2 The results of multifactor analysis of the severity of portal vein thrombosis in cirrhosis showed that:the PVT grade of patients with short course of cirrhosis(≤1 year)(OR=0.43,95%CI:-1.686,-0.003),no spongiform change(OR=0.30,95%CI:-2.186,-0.221),no endoscopic ligation/sclerosis(OR=0.10,95%CI:2.151,-2.431),and no splenectomy/embolization(OR=0.06,95%CI:-5.301,-0.252)was lower;Patients with acute symptomatic PVT stage(OR=0.13,95%CI:-3.581,-0.432),PT≥16S(OR=3.37,95%CI:0.28,2.147),and INR between 1.2-1.4(OR=0.29,95%CI:-2.414,-0.071)had higher PVT grade of thrombosis.3.The analysis results of influencing factors of PVT outcome showed that the presence or absence of endoscopic ligation(χ2=7.464),presence or absence of hepatic encephalopathy(χ2=6.591),normal creatinine(χ2=7.296),and high or low INR(χ2=13.588)had an impact on the recanalization outcome of thrombus(p<0.05).Conclusion1.Liver cirrhosis PVT often occurs in the decompensated stage,and the clinical symptoms are mainly nonacute.2.Endoscopic ligation/sclerotherapy,splenectomy/splenic embolization,spongiform transformation,long course of liver cirrhosis,and prolongation of prothrombin time are the factors of PVT occurrence and aggravation;Influential factors of endoscopic ligation/sclerotherapy,hepatic encephalopathy,increased INR and creatinine on the progression of thrombosis;3.The effective rate of PVT anticoagulant therapy in liver cirrhosis is low,which may be related to the liver reserve function,thrombosis time,and drug intervention measures.Part Ⅱ Establishment of an animal model of portal vein thrombosis and experimental study of PVT recanalizationObjectiveObjective is to construct a PVT experimental rat model and explore the clinical efficacy of rivaroxaban on PVT.Method1.Purchase 40 SPF grade SD rats,female;Weight:160g-180g.One week after adaptive feeding,the rats were randomly divided into a model group and a blank control group,with 34 rats in the model group and 6 rats in the blank control group.2.Portal vein thrombosis model rats were established,30 rats were successfully established,and 4 rats died.3.One week after modeling,the rats underwent a color Doppler ultrasound examination of the liver.Six rats without thrombus were excluded,and 24 rats entered the anticoagulation treatment experiment.The model rats were divided into model control group,model recovery group(the rats had strong self-healing ability after modeling,and for the rigor of experimental design,the model natural recovery group was established,which was defined as the model recovery group),and rivaroxaban group.There were 6 rats in the model control group,6 rats in the model recovery group,and 12 rats in the rivaroxaban group.4.Anticoagulant therapyRivaroxaban group:rivaroxaban 1.33mg·kg-1 was administered by gavage for 2 weeks.Three rats died during gastric perfusion in the rivaroxaban group.Blank control group and model recovery group:2ml normal saline was given by gavage.Gavage for 2 weeks.5.Observation indexes portal vein color Doppler ultrasound,alt,AST,AKP,TBIL,Cr,albumin,globulin,coagulation factor Ⅷ,D-dimer,P-selectin,coagulation factor Xa,vWF,IL-6,TNF-α And a histopathological examination of the portal vein.Results1.Biochemical index results:only the serum globulin of the blank control group was significantly different from that of other groups(P<0.05),and there was no significant difference among other index groups.After statistical treatment,there was no significant difference in enzyme indexes,related coagulation factors,and inflammatory factors between the blank control group,model control group,model recovery group,and rivaroxaban group before and after treatment(P>0.05).2.The curative effect of portal vein thrombosis recanalization was judged:9 cases in the rivaroxaban group,3 cases in complete recanalization,1 case in partial recanalization,and 5 cases in stability;In the model recovery group,there were 6 cases,0 cases of complete recanalization,1 case of partial recanalization,and 5 cases of stability.It suggested that the PVT recanalization efficiency of the rivaroxaban group was 44.4%.3.Portal vein histopathology:The staining showed that the thickness and structure of intima,media,and adventitia in the blank control group were normal.The model control group and model recovery group:the wall of the portal vein was significantly thickened,thrombus,lamellar fibrin,lamellar red blood cells,and endothelial cell proliferation were seen in the lumen,the media was thickened,edema and cystic change,and the outer membrane red blood cells exuded.Rivaroxaban group:thrombus could be seen in portal vein lumen in 5 cases,thrombus disappeared in 3 cases,a small amount of thrombus could be seen in 1 case,lamellar fibrin and lamellar red blood cells could be seen,endothelial cell edema and proliferation,media thickening,edema and red blood cell exudation,adventitial red blood cell exudation.Masson and VG double fiber staining showed that in the blank control group:the smooth muscle cells of the tunica media were arranged clearly,and no obvious collagen fibers were found.The model control group and model recovery group:thrombus in the lumen,thickening of the tunica media,attachment of a large number of collagen fibers,and no obvious smooth muscle cells.Rivaroxaban group:thrombus could be seen in portal vein lumen in 5 cases,thrombus disappeared in 3 cases,and a small amount of thrombus in 1 case.Smooth muscle cells are attached by collagen fibers.The structure of the tunica media was loose,and neovascularization was seen in the tunica media in 3 specimens,suggesting a cavernous transformation of the portal vein.Conclusion1.The portal vein ligation and clamp modeling method can realize pathological changes such as slow portal vein blood flow,vascular endothelial cell and smooth muscle injury,and portal vein thrombosis.2.Portal vein tissue fiber staining confirmed that the modeling method of simulating slow portal vein blood flow and vascular endothelial injury can achieve pathological changes such as portal vein wall thickening,endothelial cell proliferation,and media collagen fiber attachment.And the portal vein wall and thrombus pathology can last for at least 3 weeks;3.Oral rivaroxaban anticoagulant can achieve PVT recanalization in rats. |
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