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Publications > Journals > Journal of Clinical and Translational Hepatology> Article Full Text

  • Review Article
  • OPEN ACCESS

Portal Vein Thrombosis in Liver Cirrhosis: A Review of Risk Factors and Predictive Indicators

  • Zhicheng Yang1,#,
  • Yongle Zhao1,#,
  • Honglin Chen1,
  • Han Zhang1,
  • Maoting Tan1,
  • Xianliu Li1,
  • Lingling Tao1 and
  • Hongyun Zhao1,2,* 
 Author information 

Abstract

Actively identifying the risk factors and predictive indicators associated with portal vein thrombosis (PVT) in liver cirrhosis (LC) can enable early diagnosis and treatment, which is of great significance for prolonging the survival of patients with LC. Hemodynamic disturbances, advanced LC, vascular endothelial injury, and mutations in thrombophilic genetic factors are established risk factors for PVT-LC. Venous dilatation and decreased blood flow velocity contribute to hemodynamic disturbances. The severity of LC can be assessed by the degree of portal hypertension, liver metabolic function biomarkers, and validated liver scoring systems. Iatrogenic interventions, endotoxemia, and metabolic syndrome may induce vascular endothelial injury and hypercoagulability, the latter of which can be quantified via coagulation-anticoagulation-fibrinolysis biomarkers. Mutations in thrombophilic genetic factors, such as Factor V Leiden, MTHFR C667T, and JAK2 V617F, disrupt coagulation-anticoagulation homeostasis and predispose patients to PVT-LC. This review specifically focuses on comprehensively delineating established risk factors and predictive indicators for PVT-LC, thereby providing a theoretical foundation for the construction of clinically applicable PVT predictive models to guide early interventions and improve the prognosis. Future research should further validate the associations between recently proposed risk factors and PVT-LC, while simultaneously establishing cutoff values for indicators with robust predictive value to construct a clinically applicable PVT prediction framework.

Graphical Abstract

Keywords

Hemodynamics, Hypertension, Liver cirrhosis, Metabolic syndrome, Portal vein thrombosis, Prediction algorithms, Risk factors, Thrombophilia

Introduction

Liver cirrhosis (LC) represents the terminal stage of chronic liver disease, pathologically characterized by extensive hepatocyte degeneration and necrosis, fibrous tissue proliferation, and the formation of pseudolobules. Clinically, it is accompanied by a variety of complications, such as ascites, esophagogastric varices, hepatic encephalopathy, and portal vein thrombosis (PVT).1 PVT is defined as the presence of a thrombus within the main portal vein and may be accompanied by thrombosis in the intrahepatic and extrahepatic branches (mesenteric vein and splenic vein) of the portal vein.2

Historically, PVT-LC has been considered a relatively uncommon condition in clinical practice. Nevertheless, the development of imaging diagnostic techniques in recent years has led to a marked increase in the detection rate of PVT-LC.3 Previous studies have shown that the estimated incidence of PVT-LC ranges from 0.6% to 26%,4 with incidence positively correlating with disease severity. The incidence of PVT in patients with compensated LC is approximately 10%, while in candidates for liver transplantation, it can be as high as 26% to 30%.2,5

PVT can exacerbate portal hypertension (PH) in patients with LC, further inducing or aggravating other complications such as refractory ascites, esophagogastric variceal hemorrhage (EVH), and hepatic encephalopathy.2 Unfortunately, PVT-LC often has an insidious onset, with only a very small number of patients diagnosed and treated promptly due to symptoms arising during hospitalization. The majority of patients have already missed the optimal treatment window by the time the condition is discovered, resulting in shortened survival and poor prognosis. Therefore, actively identifying risk factors and predictive indicators associated with PVT-LC can enable early diagnosis and treatment, which is of great significance for improving the prognosis of patients with LC.

We categorize the risk factors for PVT-LC into four aspects (Fig. 1) in an attempt to elucidate its mechanisms of occurrence and uncover potential predictive indicators.

Risk factors for PVT-LC.
Fig. 1  Risk factors for PVT-LC.

CAF, coagulation-anticoagulation-fibrinolysis; CTP, Child-Turcotte-Pugh; F II G20210A, factor II gene mutation at position 20210 (G→A); FV, factor V Leiden; JAK2 V617F, Janus kinase 2 valine-to-phenylalanine mutation at position 617; LC, liver cirrhosis; MELD, model for end-stage liver disease; MTHFR C667T, methylenetetrahydrofolate reductase gene mutation at position 677 (C→T); PVT, portal vein thrombosis; THBD, thrombomodulin gene.

Hemodynamic disturbance

Vascular dilation and decreased blood flow velocity can induce PVT by causing hemodynamic disturbances, with specific mechanisms primarily including blood stasis and vortex formation.

Decreased portal vein velocity (PVV)

Decreased PVV is one of the most extensively studied and widely recognized risk factors for PVT-LC.6 A matched case-control study conducted by Stine et al.,5 which included 100 cirrhotic patients, demonstrated that PVV is an independent risk factor with the highest predictive value among the factors examined. Patients with PVV < 15 cm/s had a significantly increased risk of PVT compared to those with PVV ≥ 15 cm/s (HR = 6.00, 95% CI: 2.20–16.40, P ≤ 0.001). A meta-analysis conducted by Giri et al.7 also confirmed that PVV < 15 cm/s was the most commonly used cutoff for predicting PVT. In another case-control study involving 562 cirrhotic patients undergoing splenectomy combined with esophagogastric devascularization, the incidence of PVT was significantly higher in patients with PVV ≤ 16.5 cm/s compared to those with PVV > 16.5 cm/s (76.2% vs. 8.5%, P < 0.0001).8 These results indicate that decreased PVV remains an independent risk factor for PVT even in patients who have undergone surgical interventions.

According to Virchow’s triad, blood stasis caused by decreased blood flow velocity leads to an increased concentration of local coagulation factors and prolonged contact time between platelets and the vessel wall, thereby promoting thrombus formation. Researchers have speculated that certain medications that reduce PVV may also be associated with PVT development. Zampino et al.9 suggested that non-selective beta-blockers (NSBBs), used to treat PH and prevent variceal bleeding in patients with LC, might contribute to PVT by reducing PVV (P = 0.0003). A prospective longitudinal study conducted by Nery et al.10 confirmed that NSBB use is a risk factor for PVT, although this effect does not appear to be directly related to decreased PVV.

A recent prospective study investigated the relationship between relative residence time measured by 4D flow MRI and PVT-LC, suggesting that decreased relative residence time could serve as a novel indicator reflecting portal flow stasis, with potential predictive value.11

Portal vein dilation

Reducing PVV is considered the primary mechanism by which portal vein dilation induces PVT-LC. Furthermore, other researchers believe that the normal physiological function of the portal vein valve is to prevent backflow of blood into the portal vein from the liver. When the portal vein dilates, the valve becomes relatively insufficient, leading to an increase in the volume of blood flowing back into the portal vein and the formation of vortices. These vortices prolong the contact time between thrombin and the vascular endothelium, increasing the risk of developing PVT.12,13

Previous studies focusing on portal vein dilation have primarily revealed its close association with PVT after splenectomy. Qian et al.14 conducted a case-control study involving 130 post-splenectomy patients, which showed a statistically significant difference in preoperative portal vein diameter (PVD) between the PVT and non-PVT groups (14.8 ± 1 mm vs. 13.1 ± 1.9 mm, P = 0.000). A recent study by Wang et al.8 indicated that portal vein dilation significantly increases the risk of PVT (OR = 3.33, 95% CI: 1.81–6.13, P < 0.001). The study also proposed that PVD > 14.5 mm serves as a cutoff value for predicting PVT, consistent with the research of Nie et al.15 Additionally, a meta-analysis by Giri et al.7 demonstrated that for every 1 mm increase in PVD, the probability of PVT increases by 1.7 times.

Decreased splenic vein velocity and splenic vein dilation

In addition to hemodynamic disturbances within the portal vein, the relationship between hemodynamic disturbances in the splenic vein and PVT-LC after splenectomy has also become a focus of current research.

Previously, Kuroki et al.16 found that all cirrhotic patients postoperatively developed splenic vein thrombosis (SVT). However, only half of these patients had thrombosis in both the splenic vein and the portal vein. Notably, there were no patients who developed thrombosis solely in the portal vein without concurrent SVT. Therefore, thrombosis in the portal system after splenectomy initially occurs in the splenic vein and subsequently extends to the portal vein. In this single-center retrospective analysis, researchers also determined that splenic vein dilation is the strongest predictor for isolated SVT and for progression of SVT to PVT, with cutoff values of 10 mm and 14 mm, respectively. Later, Li et al.17 demonstrated that the splenic vein diameter in the PVT group (11.59 ± 1.65 mm) was significantly larger than in the non-PVT group (10.46 ± 1.67 mm) following laparoscopic splenectomy (P < 0.001). More recently, a single-center retrospective study by Katano et al.18 indicated that splenic vein dilation is an independent risk factor for PVT after combined liver and spleen resection (OR = 1.53, 95% CI: 1.156–2.026, P = 0.003). Although these latter two studies confirmed the association between increased splenic vein diameter and PVT after splenectomy, the cutoff values proposed by Kuroki et al. require further validation.

Vascular endothelial injury and hypercoagulable state

Factors that damage the vascular endothelium include iatrogenic interventions, portal vein inflammation caused by endotoxemia, and metabolic syndrome, all of which can also contribute to a hypercoagulable state.

Iatrogenic interventions

When LC is complicated by conditions such as PH, ascites, or EVH, endoscopic or surgical interventions are often required. These procedures have been identified as potential risk factors for PVT-LC.19–21

Splenectomy not only reduces portal venous pressure, effectively alleviating complications of LC, but also increases hepatic arterial blood flow by cutting off the splenic artery, thereby improving liver function.22 Consequently, it is one of the most commonly used surgical treatments for LC and its associated complications. A retrospective study involving 113 cirrhotic patients showed that splenectomy increased the risk of PVT by at least 10-fold.23 A case-control study by Xu et al.24 also found that a history of splenectomy was significantly associated with PVT (OR = 7.565, 95% CI: 1.514–37.799, P = 0.014). Proposed mechanisms by which splenectomy promotes PVT include: (1) Blood stasis: Splenectomy reduces portal venous blood flow and pressure, slowing portal circulation. Additionally, ligation of the splenic vein creates a residual blind end prone to blood pooling. (2) Vascular endothelial injury: Surgical manipulation, such as traction and ligation of the splenic pedicle, can damage the vascular endothelium, thereby activating the coagulation system. (3) Hypercoagulable state: After surgery, reduced platelet destruction due to hypersplenism leads to a rebound increase in platelet count and enhanced platelet aggregation.25–28

Beyond splenectomy, researchers have extensively studied the association between endoscopic treatments and PVT-LC. Endoscopic variceal ligation (EVL) and sclerotherapy are both standard treatments for EVH and effectively achieve hemostasis.29 A retrospective study in Spain found that EVL and sclerotherapy increased the risk of PVT (OR = 2.3, 95% CI: 1.2–4.5, P = 0.01).30 A case-control study by Wang et al.31 showed that, compared to the non-PVT group, the PVT group had a significantly higher proportion of patients who underwent EVL alone (19.3% vs. 9.2%, P = 0.033) or EVL combined with endoscopic cyanoacrylate injection (24.8% vs. 5.5%, P < 0.001). Endoscopic treatments primarily increased the risk of thrombosis in the extrahepatic portal system (main portal vein, superior mesenteric vein, and splenic vein), with minimal impact on the intrahepatic portal system (left and right branches of the portal vein). Some researchers have suggested that endoscopic treatments can obstruct blood flow from the portal vein to the esophagogastric collateral circulation, which increases portal venous pressure and promotes vortex formation.31 Others proposed that ligation of esophageal varices or injection of sclerosing agents can mechanically damage the vascular endothelium, activating the coagulation system.32 Therefore, when employing invasive measures to treat complications of LC, clinicians should strictly adhere to indications and carefully weigh the risks and benefits.

Endotoxemia and inflammation

Patients with advanced LC are prone to portal vein endotoxemia due to bacterial translocation from the gut and spontaneous bacterial peritonitis, making the portal system an inflammatory vascular bed. Current research suggests that inflammation caused by endotoxemia may induce PVT-LC through the following mechanisms: (1) Vascular endothelial injury: Neutrophils activated by inflammation can severely damage the membranes of vascular endothelial cells via strong oxidative bactericidal effects.33 (2) Hypercoagulable state: Endotoxin has been described as a trigger for the coagulation cascade, activating platelets and increasing thrombin levels. Cytokines induced by endotoxin can also stimulate endothelial cells to produce factor VIII.34–36 (3) PH: Endotoxemia can promote liver fibrosis and angiogenesis by activating hepatic stellate cells and Kupffer cells, as well as pro-inflammatory cytokine signaling, thereby increasing intrahepatic portal pressure.37

Previous studies have shown that whether endotoxemia can induce PVT depends on the source of the endotoxin in the portal system. An early study involving 49 cirrhotic patients found that endotoxemia caused by intestinal barrier disruption and endotoxin translocation from the gut was not a risk factor for PVT-LC,38 consistent with a recent cross-sectional study.39 In contrast, Koumar et al.40 found that endotoxemia due to spontaneous ascitic fluid infection was significantly associated with PVT.

Bacterial endotoxins induce a range of inflammatory cell and cytokine responses in the body. Accordingly, researchers are exploring the relationship between post-infection inflammatory markers and PVT to identify potential predictors. A matched case-control study by Nie et al.,15 involving 572 LC patients, combined plasma aspartate aminotransferase activity (reflecting local hepatic inflammatory damage) with neutrophil count (reflecting systemic inflammation) to develop the aspartate aminotransferase-to-neutrophil ratio index. The study found that the aspartate aminotransferase-to-neutrophil ratio index was significantly higher in the PVT group compared to the non-PVT group (40.18 vs. 27.31, P = 0.011). Xing et al.41 conducted a retrospective study on the relationship between systemic inflammatory markers and PVT, using univariate and multivariate logistic regression analyses. Univariate analysis revealed that a high systemic immune-inflammation index, neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio, and platelet-to-lymphocyte ratio (PLR) were significantly associated with PVT. Multivariate analysis identified NLR and PLR as independent risk factors for PVT (P < 0.05). The researchers proposed using a practical nomogram based on NLR and PLR to predict PVT accurately.

Novel inflammatory markers have also emerged as a current research hotspot. Serag et al.42 proposed that phosphatidylserine-positive microparticles (PS+MPs) mediate pro-inflammatory responses, vascular endothelial injury, and a hypercoagulable state during liver fibrosis. Hepatocyte damage caused by inflammation and endotoxemia can further elevate PS+MP levels. In their study, cirrhotic patients with PVT had higher PS+MP levels than those without PVT. Recent studies have also highlighted the critical regulatory role of neutrophil extracellular traps (NETs) in shaping the inflammatory microenvironment and inducing a hypercoagulable state. Plasma markers of NETs include cell-free DNA, histone-DNA complexes, and deoxyribonuclease activity. Han et al.43 found that an imbalance in NETs homeostasis (characterized by elevated cell-free DNA and histone-DNA complex levels and reduced deoxyribonuclease activity) was significantly associated with PVT in patients with decompensated LC. A recent study also hypothesized that NSBBs may promote PVT development by stimulating neutrophils to release NETs.44 Although the predictive utility of these novel inflammatory markers for PVT-LC requires further validation, clinicians should begin closely monitoring inflammatory indicators in cirrhotic patients to aid in early PVT prevention.

Metabolic syndrome

Metabolic syndrome, which significantly impacts health, is defined as a clinical condition characterized by the clustering of abdominal obesity, abnormal blood glucose, dyslipidemia, and hypertension.45 A considerable proportion of cirrhotic patients are found to have metabolic syndrome,46 and numerous studies have identified a close relationship between metabolic syndrome and PVT.

Diabetes is the most extensively studied risk factor in previous research (Table 1).13,21,40,47–49

Table 1

The association between DM and PVT-LC: an overview of case-control studies

First author, yearDM% in PVT groupDM% in no PVT groupP-valueOR, 95% CIP-value
Abdel-Razik,13 201576.5% (13/17)42.3% (33/78)<0.0012.15, 1.315–6.0130.01
Ghabril,47 201629.2% (953/3,321)22% (9,813/45,249)<0.0011.21, 1.07–1.360.002
Eshraghian,48 201837.7% (63/174)22.7% (189/833)<0.0011.366, 0.382–1.9960.748
Montenovo,49 201831.3% (1,665/5,319)23.9% (13,865/58,012)<0.0011.22, 1.13–1.32<0.001
Faccia,21 202220.94% (80/382)13.66% (952/6,968)0.00011.68, 1.27–2.220.0001
Koumar,40 20236.3% (1/16)20% (20/77)0.108

CI, confidence interval; DM, diabetes mellitus; OR, odds ratio; PVT, portal vein thrombosis; LC, liver cirrhosis.

Possible mechanisms by which diabetes induces PVT include: (1) Vascular endothelial injury: Normal vascular endothelial cells exert anticoagulant effects by synthesizing thrombomodulin. Hyperglycemia can damage vascular endothelial cells via the oxygen free radical pathway, weakening their anticoagulant function.50 (2) Hypercoagulable state: Chronic hyperglycemia leads to glycation of various proteins, inducing peripheral mononuclear cells to produce tissue factor. In addition, diabetic patients often exhibit elevated plasma levels of coagulation factors V and VIII, and enhanced platelet aggregation.51,52 Blood clots formed under hyperglycemic conditions are also more resistant to plasmin and oxidative degradation.12

Some scholars believe that the shear stress generated by turbulent blood flow in hypertension can damage vascular endothelial cells, potentially inducing PVT.53 A recent study showed no significant difference in hypertension between PVT and non-PVT groups (OR = 0.78, 95% CI: 0.59–1.03, P = 0.079).54 Previous studies have reported that visceral fat and abdominal obesity are independent risk factors for PVT.55,56 Basaranoglu57 proposed that abdominal obesity may induce PVT through pro-inflammatory factors released by abdominal adipose tissue, but this hypothesis requires further validation.

Abnormal coagulation-anticoagulation-fibrinolysis biomarkers

The hypercoagulable state of blood can be reflected by coagulation-anticoagulation-fibrinolysis biomarkers. Variations in these biomarkers can be used to determine whether a patient is prone to thrombosis and thus predict PVT-LC (Fig. 2).

Variations in CAF biomarkers used to predict PVT-LC.
Fig. 2  Variations in CAF biomarkers used to predict PVT-LC.

↑ indicates the increased level of a biomarker can predict PVT, ↓ indicates a decreased level can predict PVT. The dashed white box represents the physiological balance between vWF and ADAMTS-13 under normal conditions. ADAMTS-13, a disintegrin and metalloproteinase with thrombospondin motifs 13; AT III, antithrombin III; CAF, coagulation-anticoagulation-fibrinolysis; CD62P, P-selectin; FDP, fibrin degradation products; F VIII, factor VIII; MPV, mean platelet volume; PC, protein C; PS, protein S; TGF-β1, transforming growth factor-β1; vWF, von Willebrand factor; PVT, portal vein thrombosis; LC, liver cirrhosis.

D-dimer and fibrin degradation products (FDP) are specific biomarkers formed after the degradation of fibrin in thrombi. Elevated levels reflect both a hypercoagulable state and secondary hyperfibrinolysis.58,59 D-dimer participates in the early stages of thrombus formation, accelerating PVT development.60 Multiple studies have confirmed that D-dimer is an independent risk factor for PVT-LC and can serve as an effective predictor.58,59,61–63 A recent retrospective study by Yang et al.60 quantified D-dimer levels associated with PVT-LC and found that levels exceeding 0.87 µg/mL were an independent risk factor (OR = 1.925, 95% CI: 1.538–2.410, P = 0.000). It is important to note that D-dimer levels can also rise in various stress conditions such as pregnancy, major surgery, and infections, making it non-specific. Therefore, diagnosing PVT using D-dimer requires comprehensive analysis in conjunction with other diagnostic markers.28 In contrast, research on FDP remains relatively limited. A single-center case-control study by Lin et al.64 found that higher FDP levels were associated with a greater incidence of PVT (18.57 ± 19.46 µg/mL vs. 5.45 ± 6.00 µg/mL, P < 0.05), a finding that requires further validation in larger, multi-center studies.

Platelets, one of the main components of thrombi, also play a crucial role in the coagulation process. Activated platelets not only provide a catalytic surface for coagulation-related enzymes to promote clotting but also release antifibrinolytic factors (such as α-antiplasmin) to inhibit fibrinolysis and stabilize clots. Multiple studies have observed lower platelet counts in cirrhotic patients with PVT,13,27,64 likely due to increased platelet destruction by the hyperactive spleen. A recent study demonstrated that cirrhotic patients exhibit highly activated platelet function, which promotes thrombus formation.65 Therefore, platelet activation, rather than platelet count, better explains PVT in the context of low platelet levels.

Researchers have thus turned to biomarkers reflecting platelet activation to predict PVT. An early prospective study found that mean platelet volume (MPV) was significantly higher in the PVT group compared to the non-PVT group (8.3 ± 0.54 fL vs. 7.7 ± 0.65 fL, P < 0.001).13 Elevated MPV indicates enhanced platelet function, which leads to the release of more thromboxane A2, promoting thrombus formation.13 A subsequent meta-analysis by Lin et al.66 supported this conclusion, suggesting MPV is an early marker of platelet activation. Additionally, Jiang et al.67 found that elevated platelet-derived transforming growth factor-beta 1 may induce PVT-LC by interfering with vascular endothelial cell function. Some researchers also believe that P-selectin (CD62P), a marker of platelet activation on the platelet surface, may serve as a predictor of PVT-LC.68

Fibrinogen, the most abundant coagulation factor in plasma, plays a critical role in coagulation. Previous studies suggest that it is not fibrinogen levels but its structural and functional changes that are closely related to PVT.69 Hugenholtz et al.70,71 proposed that oxidative modifications in chronic liver disease alter fibrinogen’s structure, leading to the formation of fibrin clots with reduced permeability and diminished interaction with plasmin, resulting in thrombi less susceptible to degradation.

Cirrhotic patients, due to decreased liver synthetic function, experience reduced synthesis of both coagulation and anticoagulation factors, placing the body in an unstable coagulation-anticoagulation balance that can be disrupted by various risk factors.19 Reduced synthesis of anticoagulation factors such as antithrombin III, protein C (PC), and protein S can induce PVT-LC, as confirmed by related studies.58,72 A meta-analysis incorporating 10 original studies demonstrated that cirrhotic patients with PVT have a significantly higher F VIII/PC ratio (factor VIII to protein C) (P = 0.00).73

von Willebrand factor (vWF), a plasma glycoprotein involved in hemostasis, primarily functions in platelet adhesion and aggregation. A disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS-13) is a protease that cleaves vWF, preventing platelet aggregation and thrombus formation. Under normal conditions, a balance is maintained between vWF and ADAMTS-13. A prospective study by Sacco et al.74 found that imbalance between vWF and ADAMTS-13 in LC is a significant risk factor for PVT, and an ADAMTS-13/vWF ratio < 0.4 may be a reliable predictor of PVT development, though further validation is needed.

Severity of LC

PVT is a complication of LC, and thus, the severity of LC is likely one of the risk factors for PVT. The severity of LC can be reflected by the degree of PH, laboratory indicators related to hepatic metabolic function, and liver function scoring models.

Severe PH and complications

PH is a common clinical manifestation of decompensated LC, capable of inducing severe complications such as ascites, hepatic encephalopathy, and EVH.75 As such, PH can reflect the severity of LC. The severity of PH is considered one of the most fundamental risk factors associated with PVT-LC.76 The mechanism by which PH contributes to PVT is primarily thought to involve compensatory splanchnic arterial vasodilation and the formation of porto-collateral vessels, which lead to blood shunting and reduced portal flow.77 A vicious cycle may exist between PH and PVT: PH promotes the formation of PVT, while PVT induces portal vein stenosis and blood stasis, further increasing portal venous pressure. The hepatic venous pressure gradient (HVPG) is the best indirect indicator for measuring portal venous pressure. However, there is currently no consensus on the predictive cutoff value for HVPG. In Turon’s study, patients with HVPG > 20 mmHg had a higher incidence of developing PVT than those with HVPG < 20 mmHg (HR = 8.08, P = 0.015, 95% CI = 1.50–43.6).78 Meanwhile, a recent study demonstrated that HVPG ≥ 16 mmHg can serve as an independent predictor of PVT (P = 0.011).79

Complications related to PH have been confirmed by many researchers to be associated with PVT-LC.80 A single-center study found that cirrhotic patients with ascites had a higher incidence of PVT compared to those without ascites, and that incidence increased with the severity of ascites.81 A retrospective study by Ak et al.,82 which included 165 cirrhotic patients undergoing liver transplant evaluation, demonstrated that a history of EVH significantly increased the risk of PVT (OR = 3.45, 95% CI = 1.02–11.6, P = 0.046). A prospective cohort study also showed that the incidence of PVT was significantly higher in patients with hepatic encephalopathy (38.1% vs. 9.9%, P = 0.01).83 Therefore, early clinical monitoring of portal venous pressure and proactive prevention of related complications may be effective measures to reduce the incidence of PVT-LC.

Certain laboratory indicators can indirectly reflect the presence of complications related to PH and may serve as predictive factors for PVT-LC. Hypersplenism and EVH caused by PH increase erythrocyte destruction and loss, lowering hemoglobin and hematocrit levels.13,84 In a retrospective study conducted by Cagin et al.,85 hematocrit levels in the PVT group were significantly lower than in the non-PVT group(34.32% vs. 38.4%, P < 0.001). Lopez-Gomez et al.83 also observed that hemoglobin levels were significantly lower in the PVT group than in the non-PVT group (12.6 g/dL vs. 13.8 g/dL, P = 0.01).

Abnormal laboratory indicators reflecting liver metabolic function

Plasma albumin (Alb), a protein synthesized by hepatocytes, reflects the liver’s synthetic function. In patients with LC, the liver’s synthetic function is impaired, and although nutrient intake may be sufficient, symptoms like poor appetite lead to lower Alb levels. A retrospective study involving 98 cirrhotic patients with PVT and 101 cirrhotic patients without PVT showed significant differences in Alb levels (2.97 g/L vs. 3.2 g/L, P < 0.05),85 consistent with the study by Gîrleanu et al.86 Notably, Basili et al.87 demonstrated that Alb can inhibit platelet activation by suppressing oxidative stress mediated by soluble Nox2-derived peptides, further supporting the hypothesis that hypoalbuminemia is a risk factor for PVT.

The associations between bilirubin (BIL) and low blood urea nitrogen (BUN) levels and PVT-LC remain controversial, warranting further research. Cagin et al.85 found that BIL levels in cirrhotic patients with PVT were significantly higher than in those without PVT (2.805 mg/dL vs. 1.6 mg/dL, P < 0.001). Yang et al.60 proposed that higher BUN levels increased the risk of PVT (OR = 1.1157, 95% CI = 1.247–1.306, P = 0.018). In contrast, a retrospective study by Li et al.61 found that BIL levels were significantly lower in the PVT group compared to the non-PVT group (12.7 µmol/L vs. 15.4 µmol/L, P = 0.004), and that lower BUN levels were independently associated with PVT (4.75 mmol/L vs. 5.2 mmol/L, P = 0.006), contradicting the aforementioned studies. Additionally, Lopez-Gomez et al.83 did not find a statistically significant difference in BIL levels between the PVT and non-PVT groups.

A possible explanation is that the relationship between BIL and BUN levels and the risk of developing PVT follows a U-shaped curve. Specifically, both lower and higher levels of BIL and BUN may contribute to PVT development. Urea is the primary end product of protein metabolism in the liver, and BUN levels may indirectly reflect poor overall nutritional status and decreased liver metabolic function.61 On the other hand, in patients with advanced cirrhosis complicated by hepatorenal syndrome, BUN levels may elevate due to reduced renal clearance of urea. As for BIL, in the early stages of cirrhosis, hemolysis due to hypersplenism and decreased hepatic metabolic function from hepatocyte damage can increase the production and reduce the excretion of BIL, resulting in elevated BIL levels. In late-stage disease, the number of red blood cells declines due to prior destruction, reducing the production of BIL from its source and consequently leading to decreased BIL levels.

High Child-Turcotte-Pugh (CTP) and Model for End-Stage Liver Disease (MELD) score

The CTP score is one of the most widely used clinical tools for assessing hepatic reserve function. It incorporates complications of cirrhosis (ascites, hepatic encephalopathy), indicators reflecting hepatic metabolic function (BIL, Alb), and a hemostatic parameter (prothrombin time) to comprehensively estimate the risk of PVT-LC. Based on the total score, liver function is classified into three grades: A, B, and C. A meta-analysis by Pan et al.88 indicated that CTP B and C can predict the occurrence of PVT-LC. The liver has dual roles in synthesizing both procoagulant and anticoagulant substances. The higher the CTP score, the worse the liver reserve function, leading to reduced synthesis of both pro-coagulant and anticoagulant substances. However, the reduction in anticoagulant synthesis appears greater than that of pro-coagulant substances, resulting in a prothrombotic state. This prothrombotic tendency gradually worsens from CTP A to C.89 Notably, a prospective study found that not all patients with advanced LC develop PVT: only about 50% of patients in CTP C had PVT. Moreover, in that study, the CTP score worsened significantly compared to baseline after the occurrence of PVT. Therefore, the researchers speculated that the elevated CTP score might be a consequence of the formation and progression of PVT.90

Given the limitations of the CTP classification, researchers have also explored the clinical value of the MELD, proposed by Malinchoc et al. in 2000, for predicting PVT-LC. Compared to the CTP score, the MELD score incorporates more laboratory indicators (serum creatinine, international normalized ratio) and excludes factors such as hepatic encephalopathy and ascites, which are influenced by subjective clinical evaluation, holding greater clinical utility. Noronha et al.91 confirmed that the MELD score could independently predict decompensated LC (HR = 1.14, 95% CI: 1.09–1.19) and, consequently, the occurrence of non-neoplastic PVT. Recently, a single-center retrospective study also found significant differences in both CTP and MELD scores between the PVT and non-PVT groups (P = 0.03 and P = 0.01, respectively).81 Overall, in assessing LC severity, the MELD score is less widely used than the CTP score due to its more complex calculation. However, because it is more objective and accurate, it may offer superior predictive value for risk stratification in certain complex cases.

Ultimately, we consolidated the diagnostic utility of the aforementioned risk factors and predictive indicators for PVT-LC (Table 2).5,7,42,43,60,77,92

Table 2

The diagnostic value of risk factors and predictive indicators for PVT-LC

Risk factorsSensitivitySpecificityAUCCutoff value
NLR42––0.596≥3.14
PLR42––0.628≥103.4
PS+MPs4383.33%97.56%0.917>35.3nmol/L
PVV566.67%78.05%0.854≤15cm/L
PVD7––0.732≥14.5cm
D-dimmer6083.3%83.1%0.858>0.87g/L
Splenectomy6045.4%90.1%0.6771
HVPG7791.7%48.6%0.701≥17.52mmHg
CD62P9278.57%90.91%0.898>74.39ng/mL

AUC, area under the curve; CD62P, P-selectin; HVPG, hepatic venous pressure gradient; NLR, neutrophil-to-lymphocyte ratio; PLR, platelet-to-lymphocyte ratio; PS+MPs, phosphatidylserine-positive microparticles; PVD, portal vein diameter; PVT, portal vein thrombosis; LC, liver cirrhosis; PVV, portal vein velocity.

Mutations in thrombophilic genetic factors (THRGFs)

Previous studies have shown that a significant proportion of cirrhotic patients with PVT carry THRGFs.85 Searching for relevant genes is currently one of the major research hotspots (Table 3).93–102

Table 3

The THRGFs currently known: an overview of previous studies and case reports

First author, yearJournalTHRGFMechanisms leading to PVT
Bertina,93 1994NatureFV LeidenLeading to activated PC resistance
Frosst,94 1995Nat. Genet.MTHFR C677TAssociating with low levels of NO (a vasodilatory factor) and hyperhomocysteinemia
Ohlin,95 1997Thromb Haemost.THBDTM is an endothelial cell cofactor for activated protein C, the lack of TM causes impaired activation of PC
Chamouard,96 1999GastroenterologyF II G20210ALeading to elevated prothrombin levels
De Stefano,97 2007Hepatol.JAK2 V617FAssociating with myeloproliferative disorders, which increases the production of platelets and RBCs
D’Amico,98 2015GenePAI-1Inhibiting the fibrinolytic system
Plompe,99 2015Haematol.CALRAssociating with myeloproliferative neoplasms, especially essential thrombocythemia and primary myelofibrosis
Zhang,100 2020Clin Biochem.SERPINC1Causing the deficiency of AT III (a natural anticoagulant)
Zou,101 2022Exp. ther. med.PROCCausing the deficiency of PC (a natural anticoagulant)
Ye,102 2023Clin. res. hepatol. gastroenterol.PROSCausing the deficiency of PS (a natural anticoagulant)

AT III, antithrombin III; CALR, calreticulin; FV, factor V Leiden; F II G20210A, factor II gene mutation at position 20210 (G→A); MTHFR C667T, methylenetetrahydrofolate reductase gene mutation at position 677 (C→T); JAK2 V617F, Janus kinase 2 valine-to-phenylalanine mutation at position 617; NO, nitric oxide; PAI, plasminogen activator inhibitor; PC, protein C; PROC, gene for protein C; PROS, gene of protein S; PS, protein S; SERPINC1, serpin family C member 1; THBD, gene of thrombomodulin; TM, thrombomodulin.

Early studies clearly demonstrated that G20210A, FV Leiden, and MTHFR C677T mutations are closely associated with PVT-LC.103 A subsequent case-control study by Saugel et al.104 revealed a significantly higher JAK2 V617F mutation rate in the PVT group compared to the non-PVT group. A cohort study by Ames et al.105 also found that the MTHFR TT homozygous genotype may be associated with more severe LC and lower PC levels, leading to an earlier onset of PVT-LC. Whether other genetic factors are associated with PVT-LC requires further validation. It is generally believed that mutations in THRGFs cause decreased production of certain coagulation factors or inactivation of anticoagulant factors, inducing a hypercoagulable state.

Moreover, genetic polymorphisms in thrombophilic genes exhibit significant ethnic variations.106 FV Leiden and G20210A mutations are major genetic risk factors for thrombosis in Caucasian populations, whereas PROC gene mutations are more prevalent among Chinese and other Asian populations.107,108 Currently, the Caprini Risk Assessment Model includes Factor V Leiden and prothrombin G20210A mutations.109 Notably, it may not be applicable to Chinese and other Asian populations.

Furthermore, unlike the well-established association of FV Leiden and G20210A with PVT-LC, studies suggest that PROC may not be involved in the pathogenesis of PVT in Chinese cirrhotic patients.110 This indicates that inherited thrombophilia might not be a major risk factor for PVT-LC in the Chinese population.111 Consequently, current genetic screening for PVT-related mutations may provide limited clinical benefits for Chinese cirrhotic patients. Future research should aim to elucidate the genetic variants causally linked to PVT development in Chinese cirrhotic patients and to establish clinically applicable genetic screening algorithms.

Clinical decision-making framework for PVT risk stratification

Based on the four major categories of risk factors described above, we propose the following clinical decision algorithm for PVT risk stratification, taking into account both the level of evidence for existing risk factors and their strength of association with PVT (Table 4).7,23–32,73,88,112 This algorithm is designed to help clinicians identify high-risk patients, tailor surveillance frequency, and optimize preventive strategies (Fig. 3). For individuals deemed at higher risk, an increased frequency of ultrasound screening is recommended, along with active consideration of anticoagulation therapy.113

Table 4

Risk stratification for PVT-LC based on the aforementioned risk factors and predictors

Risk gradeRisk factors and predictorsOR95% CIP-valueSource of evidence
High-riskPVD↑3.3301.81–6.13<0.001Meta-analysis7
Splenectomy history7.5651.514–37.7990.014Multiple analysis23–28
PVV↓6.0002.20–16.40≤0.001Multiple studies7
Medium-riskEndoscopic treatment history2.3001.2–4.50.01Multiple studies29–32
Diabetes mellitus1.8001.42–2.28<0.0001Meta-analysis112
D-dimer↑1.9251.538–2.4100Meta-analysis88
CTP B/C2.0401.40–2.95<0.001Meta-analysis88
F VIII/P C↑1.5801.17–2.140.0028Meta-analysis73
Low-riskCTP A, without high-risk and medium-risk factors

(1) High-risk: proved by meta-analysis or multiple studies and OR≥3; (2) Medium-risk: proved by meta-analysis or multiple studies and OR<3; (3) Exclusion criteria: risk factors and predictors that are unvalidated, impractical, and invasive. (e.g., BIL, ANRI and HVPG). ↑, Elevated level of a risk factor or predictor; ↓, Decreased level of a risk factor or predictor. ANRI, AST-to-neutrophil ratio index; BIL, bilirubin; CI, confidence interval; CTP-A, Child-Turcotte-Pugh Class A; CTP-B/C, Child-Turcotte-Pugh Classes B and C; F VIII/PC, ratio of factor VIII to protein C; HVPG, hepatic venous pressure gradient; OR, odds ratio; PVD, portal vein diameter; PVT, portal vein thrombosis; LC, liver cirrhosis; PVV, portal vein velocity.

Practical algorithm for early screening of PVT-LC.
Fig. 3  Practical algorithm for early screening of PVT-LC.

CTP-A, Child-Turcotte-Pugh Class A; PVT, portal vein thrombosis; LC, liver cirrhosis.

Notably, while we present a practical approach for early screening of PVT-LC based on current evidence, this framework is not yet fully optimized. First, although predictive imaging parameters (such as PVV) and laboratory markers (such as D-dimer) have demonstrated significant correlations with PVT, their precise cutoff values remain contentious. Secondly, our review incorporates a limited number of studies. Future research should focus on establishing validated cutoff values for these predictive indicators and generating more robust evidence for early PVT screening.

Conclusions

The risk factors for PVT-LC primarily fall into four categories: hemodynamic disturbances in the portal system, severe LC, vascular endothelial cell injury and hypercoagulable state, and mutations in THRGFs. It is important to note that these risk factors are not entirely independent or isolated. Instead, they are interconnected and may even mutually reinforce one another (Fig. 4). For any individual patient, the formation of PVT results from the interaction of a dominant factor with multiple additional contributing factors and mechanisms. Therefore, clinically analyzing the potential triggers of PVT-LC and preventing its occurrence requires a comprehensive consideration of all possible risk factors.

Pathogenic mechanisms and interrelationships of risk factors for PVT-LC.
Fig. 4  Pathogenic mechanisms and interrelationships of risk factors for PVT-LC.

DM, diabetes mellitus; PH, portal hypertension; PVT, portal vein thrombosis; PVT, portal vein thrombosis; LC, liver cirrhosis; PVV, portal vein velocity.

Declarations

Funding

This work was supported in part by a grant from the General Program of the Chongqing Natural Science Foundation (CSTB2022NSCQ-MSX0909 to HZ); the Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University (No. 2021240308 to HZ); and the Group Medical Aid Project for the Tibet Autonomous Region, supported by the Natural Science Foundation of the Tibet Autonomous Region (XZ2023ZR-ZY75(Z)).

Conflict of interest

The authors have no conflict of interests related to this publication.

Authors’ contributions

Providing background information and outline for the draft (ZY, YZ, HZhao), literature search (HC, HZhang), data analysis (YZ, MT, XL, LT), drawing diagrams (ZY, HC), drafting of the manuscript (ZY), and critical revision of the manuscript for important intellectual content (YZ, HZhao). All authors have made significant contributions to this study and have approved the final manuscript.

References

  1. Ginès P, Krag A, Abraldes JG, Solà E, Fabrellas N, Kamath PS. Liver cirrhosis. Lancet 2021;398(10308):1359-1376 View Article PubMed/NCBI
  2. Senzolo M, Garcia-Tsao G, García-Pagán JC. Current knowledge and management of portal vein thrombosis in cirrhosis. J Hepatol 2021;75(2):442-453 View Article PubMed/NCBI
  3. Jha RC, Khera SS, Kalaria AD. Portal Vein Thrombosis: Imaging the Spectrum of Disease With an Emphasis on MRI Features. AJR Am J Roentgenol 2018;211(1):14-24 View Article PubMed/NCBI
  4. Stotts MJ, Wentworth BJ, Northup PG. Management of Portal Vein Thrombosis in Cirrhosis. Semin Liver Dis 2021;41(1):79-86 View Article PubMed/NCBI
  5. Stine JG, Wang J, Shah PM, Argo CK, Intagliata N, Uflacker A, et al. Decreased portal vein velocity is predictive of the development of portal vein thrombosis: A matched case-control study. Liver Int 2018;38(1):94-101 View Article PubMed/NCBI
  6. Qi X, Li H, Liu X, Yao H, Han G, Hu F, et al. Novel insights into the development of portal vein thrombosis in cirrhosis patients. Expert Rev Gastroenterol Hepatol 2015;9(11):1421-1432 View Article PubMed/NCBI
  7. Giri S, Singh A, Kolhe K, Kozyk M, Roy A. Assessment of portal system hemodynamics for the prediction of portal vein thrombosis in cirrhosis-A systematic review and meta-analysis. J Clin Ultrasound 2023;51(7):1248-1258 View Article PubMed/NCBI
  8. Wang JL, Li J, Wang WQ, Lv X, Zhu RH, Yuan T, et al. Portal vein velocity predicts portal vein system thrombosis after splenectomy with esophagogastric devascularization. Surg Endosc 2024;38(2):648-658 View Article PubMed/NCBI
  9. Zampino R, Lebano R, Coppola N, Macera M, Grandone A, Rinaldi L, et al. The use of nonselective beta blockers is a risk factor for portal vein thrombosis in cirrhotic patients. Saudi J Gastroenterol 2018;24(1):25-29 View Article PubMed/NCBI
  10. Nery F, Correia S, Macedo C, Gandara J, Lopes V, Valadares D, et al. Nonselective beta-blockers and the risk of portal vein thrombosis in patients with cirrhosis: results of a prospective longitudinal study. Aliment Pharmacol Ther 2019;49(5):582-588 View Article PubMed/NCBI
  11. Hyodo R, Takehara Y, Ishizu Y, Nishida K, Mizuno T, Ichikawa K, et al. Evaluation of 4D Flow MRI-Derived Relative Residence Time as a Marker for Cirrhosis Associated Portal Vein Thrombosis. J Magn Reson Imaging 2024;60(6):2592-2601 View Article PubMed/NCBI
  12. Li T, Wang LL, Li YP, Gan J, Wei XS, Mao XR, et al. Predictors of portal vein thrombosis after splenectomy in patients with cirrhosis. World J Hepatol 2024;16(2):241-250 View Article PubMed/NCBI
  13. Abdel-Razik A, Mousa N, Elhelaly R, Tawfik A. De-novo portal vein thrombosis in liver cirrhosis: risk factors and correlation with the Model for End-stage Liver Disease scoring system. Eur J Gastroenterol Hepatol 2015;27(5):585-592 View Article PubMed/NCBI
  14. Qian YY, Li K. The early prevention and treatment of PVST after laparoscopic splenectomy: A prospective cohort study of 130 patients. Int J Surg 2017;44:147-151 View Article PubMed/NCBI
  15. Nie GL, Yan J, Li Y, Zhang HL, Xie DN, Zhu XW, et al. Predictive model for non-malignant portal vein thrombosis associated with cirrhosis based on inflammatory biomarkers. World J Gastrointest Oncol 2024;16(4):1213-1226 View Article PubMed/NCBI
  16. Kuroki T, Kitasato A, Tokunaga T, Takeshita H, Taniguchi K, Maeda S, et al. Predictors of portal and splenic vein thrombosis after laparoscopic splenectomy: a retrospective analysis of a single-center experience. Surg Today 2018;48(8):804-809 View Article PubMed/NCBI
  17. Li Y, Fu X, Li Y, Liu P, Liu S, Pan Y. Early prevention and risk factors analysis of portal vein system thrombosis after laparoscopic splenectomy and pericardial devascularization. Surg Endosc 2022;36(12):8918-8926 View Article PubMed/NCBI
  18. Katano K, Nakanuma S, Araki T, Kato K, Sugita H, Gabata R, et al. Predictors of portal vein thrombosis after simultaneous hepatectomy and splenectomy: A single-center retrospective study. Asian J Surg 2024;47(12):5137-5142 View Article PubMed/NCBI
  19. Li MX, Zhang XF, Liu ZW, Lv Y. Risk factors and clinical characteristics of portal vein thrombosis after splenectomy in patients with liver cirrhosis. Hepatobiliary Pancreat Dis Int 2013;12(5):512-519 View Article PubMed/NCBI
  20. de’Angelis N, Abdalla S, Lizzi V, Esposito F, Genova P, Roy L, et al. Incidence and predictors of portal and splenic vein thrombosis after pure laparoscopic splenectomy. Surgery 2017;162(6):1219-1230 View Article PubMed/NCBI
  21. Faccia M, Santopaolo F, Gasbarrini A, Pompili M, Zocco MA, Ponziani FR. Risk factors for portal vein thrombosis or venous thromboembolism in a large cohort of hospitalized cirrhotic patients. Intern Emerg Med 2022;17(5):1327-1334 View Article PubMed/NCBI
  22. Han JB, Shu QH, Yi YX, Sun BC. Predictors of Long-Term Rebleeding Risk in Cirrhotic Patients Undergoing Esophagogastric Devascularization and Splenectomy: Impact of Portal Vein Thrombosis and Hemoglobin Levels. Med Sci Monit 2023;29:e941153 View Article PubMed/NCBI
  23. Qi X, Han G, Ye C, Zhang Y, Dai J, Peng Y, et al. Splenectomy Causes 10-Fold Increased Risk of Portal Venous System Thrombosis in Liver Cirrhosis Patients. Med Sci Monit 2016;22:2528-2550 View Article PubMed/NCBI
  24. Xu X, Jin J, Liu Y, Li H. Analysis of related factors of portal vein thrombosis in liver cirrhosis. BMC Gastroenterol 2023;23(1):26 View Article PubMed/NCBI
  25. Mantaka A, Augoustaki A, Kouroumalis EA, Samonakis DN. Portal vein thrombosis in cirrhosis: diagnosis, natural history, and therapeutic challenges. Ann Gastroenterol 2018;31(3):315-329 View Article PubMed/NCBI
  26. Wang T, Zhou Z, Liang F. Influences of Anatomorphological Features of the Portal Venous System on Postsplenectomy Hemodynamic Characteristics in Patients With Portal Hypertension: A Computational Model-Based Study. Front Physiol 2021;12:661030 View Article PubMed/NCBI
  27. Yuan HL, Wang M, Chu WW, Li FX, Lu JJ, Li Y. Nomogram Model for Prediction of Portal Vein Thrombosis in Patients with Liver Cirrhosis After Splenectomy: A Retrospective Analysis of 2 Independent Cohorts. Med Sci Monit 2021;27:e929844 View Article PubMed/NCBI
  28. Ding J, Zhao F, Miao Y, Liu Y, Zhang H, Zhao W. Nomogram for Predicting Portal Vein Thrombosis in Cirrhotic Patients: A Retrospective Cohort Study. J Pers Med 2023;13(1):103 View Article PubMed/NCBI
  29. Zhang Q, Jin J, Zhang F, Xiang Y, Wu W, Wang Z, et al. Novel balloon compression-assisted endoscopic injection sclerotherapy and endoscopic variceal ligation in the treatment of esophageal varices: a prospective randomized study. Surg Endosc 2022;36(10):7839-7847 View Article PubMed/NCBI
  30. Reyes L, Herrero JI, Rotellar Sastre F, Páramo JA. Risk factors and impact of portal vein thrombosis in liver transplantation. Rev Esp Enferm Dig 2019;111(6):437-444 View Article PubMed/NCBI
  31. Wang L, Guo X, Shao X, Xu X, Zheng K, Wang R, et al. Association of endoscopic variceal treatment with portal venous system thrombosis in liver cirrhosis: a case-control study. Therap Adv Gastroenterol 2022;15:17562848221087536 View Article PubMed/NCBI
  32. Sugimoto K, Shiraki K, Murata K, Ito T, Ohmori S, Sakai T, et al. The effect of endoscopic injection sclerotherapy on portal blood flow and liver function. Hepatogastroenterology 2002;49(48):1587-1590 PubMed/NCBI
  33. Yang H, Liu Y, Li P, Yang S, Wang Z. Analysis of risk factors for early rebleeding from esophageal and gastric varices in patients with liver cirrhosis. J Clin Hepatol 2014;30:540-542 View Article
  34. Carnevale R, Raparelli V, Nocella C, Bartimoccia S, Novo M, Severino A, et al. Gut-derived endotoxin stimulates factor VIII secretion from endothelial cells. Implications for hypercoagulability in cirrhosis. J Hepatol 2017;67(5):950-956 View Article PubMed/NCBI
  35. Gîrleanu I, Trifan A, Stanciu C, Sfarti C. Portal vein thrombosis in cirrhotic patients - it is always the small pieces that make the big picture. World J Gastroenterol 2018;24(39):4419-4427 View Article PubMed/NCBI
  36. Violi F, Pignatelli P, Castellani V, Carnevale R, Cammisotto V. Gut dysbiosis, endotoxemia and clotting activation: A dangerous trio for portal vein thrombosis in cirrhosis. Blood Rev 2023;57:100998 View Article PubMed/NCBI
  37. Mehta G, Gustot T, Mookerjee RP, Garcia-Pagan JC, Fallon MB, Shah VH, et al. Inflammation and portal hypertension - the undiscovered country. J Hepatol 2014;61(1):155-163 View Article PubMed/NCBI
  38. Wosiewicz P, Żorniak M, Hartleb M, Barański K, Hartleb M, Onyszczuk M, et al. Portal vein thrombosis in cirrhosis is not associated with intestinal barrier disruption or increased platelet aggregability. Clin Res Hepatol Gastroenterol 2016;40(6):722-729 View Article PubMed/NCBI
  39. Aleksandrova RR, Nieuwenhuis LM, Karmi N, Zhang S, Swarte JC, Björk JR, et al. Gut microbiome dysbiosis is not associated with portal vein thrombosis in patients with end-stage liver disease: a cross-sectional study. J Thromb Haemost 2025;23(4):1407-1415 View Article PubMed/NCBI
  40. Koumar L, Senthamizhselvan K, Barathi D, Verma A, Rao P, Selvaraj J, et al. Portal Vein Thrombosis in Patients With Cirrhosis of the Liver: Prevalence and Risk Factors. Cureus 2023;15(12):e50134 View Article PubMed/NCBI
  41. Xing Y, Tian Z, Jiang Y, Guan G, Niu Q, Sun X, et al. A practical nomogram based on systemic inflammatory markers for predicting portal vein thrombosis in patients with liver cirrhosis. Ann Med 2022;54(1):302-309 View Article PubMed/NCBI
  42. Serag WM, Mohammed BSE, Mohamed MM, Elsayed BE. Predicting the risk of portal vein thrombosis in patients with liver cirrhosis and hepatocellular carcinoma. Heliyon 2020;6(8):e04677 View Article PubMed/NCBI
  43. Han M, Liu Y, Cao Y, Zhang Y, Yan Y, Deng S, et al. The Imbalance of Homeostasis in Neutrophil Extracellular Traps is Associated with Portal Vein Thrombosis in Patients with Decompensated Cirrhosis. J Clin Transl Hepatol 2024;12(12):1009-1019 View Article PubMed/NCBI
  44. Xu X, Xu S, Zhang Y, Wang L, Yan C, Xu Z, et al. Neutrophil extracellular traps formation may be involved in the association of propranolol with the development of portal vein thrombosis. Thromb Res 2024;238:208-221 View Article PubMed/NCBI
  45. Prasun P. Mitochondrial dysfunction in metabolic syndrome. Biochim Biophys Acta Mol Basis Dis 2020;1866(10):165838 View Article PubMed/NCBI
  46. Manka P, Syn WK. NASH, Metabolic Syndrome, and Diabetes: How Sugar and Fat Increase the Risk of Developing Advanced Liver Disease. Dig Dis Sci 2021;66(7):2147-2148 View Article PubMed/NCBI
  47. Ghabril M, Agarwal S, Lacerda M, Chalasani N, Kwo P, Tector AJ. Portal Vein Thrombosis Is a Risk Factor for Poor Early Outcomes After Liver Transplantation: Analysis of Risk Factors and Outcomes for Portal Vein Thrombosis in Waitlisted Patients. Transplantation 2016;100(1):126-133 View Article PubMed/NCBI
  48. Eshraghian A, Nikeghbalian S, Kazemi K, Mansoorian M, Shamsaeefar A, Eghlimi H, et al. Portal vein thrombosis in patients with liver cirrhosis and its impact on early and long-term outcomes after liver transplantation. Int J Clin Pract 2018;73:e13309 View Article PubMed/NCBI
  49. Montenovo M, Rahnemai-Azar A, Reyes J, Perkins J. Clinical Impact and Risk Factors of Portal Vein Thrombosis for Patients on Wait List for Liver Transplant. Exp Clin Transplant 2018;16(2):166-171 View Article PubMed/NCBI
  50. Wang H, Wang Z, Tang Q. Reduced expression of microRNA-199a-3p is associated with vascular endothelial cell injury induced by type 2 diabetes mellitus. Exp Ther Med 2018;16(4):3639-3645 View Article PubMed/NCBI
  51. Senzolo M. Liver: PVT in cirrhosis, not always an innocent bystander. Nat Rev Gastroenterol Hepatol 2015;12(1):11-13 View Article PubMed/NCBI
  52. Yuan J, Xu GM. Early and Late Stent Thrombosis in Patients with Versus Without Diabetes Mellitus Following Percutaneous Coronary Intervention with Drug-Eluting Stents: A Systematic Review and Meta-Analysis. Am J Cardiovasc Drugs 2018;18(6):483-492 View Article PubMed/NCBI
  53. Ruggeri P, Lo Bello F, Nucera F, Gaeta M, Monaco F, Caramori G, et al. Hereditary hyperhomocysteinemia associated with nephrotic syndrome complicated by artery thrombosis and chronic thromboembolic pulmonary hypertension: A case report. Monaldi Arch Chest Dis 2017;87(3):880 View Article PubMed/NCBI
  54. Zhang L, Wang X, Ming P, Ma LN, Ma W, Ding XC. The risk factors of liver cirrhosis complicated with portal vein thrombosis and the efficacy and safety of anticoagulant therapy: a meta analysis. Thromb J 2025;23(1):43 View Article PubMed/NCBI
  55. Ayala R, Grande S, Bustelos R, Ribera C, García-Sesma A, Jimenez C, et al. Obesity is an independent risk factor for pre-transplant portal vein thrombosis in liver recipients. BMC Gastroenterol 2012;12:114 View Article PubMed/NCBI
  56. Hernández-Conde M, Llop E, Fernández-Carrillo C, Perelló C, López-Gómez M, Abad J, et al. Visceral fat is associated with cirrhotic portal vein thrombosis. Expert Rev Gastroenterol Hepatol 2019;13(10):1017-1022 View Article PubMed/NCBI
  57. Basaranoglu M. Increased prevalence of portal vein thrombosis in patients with nonalcoholic steatohepatitis-cirrhosis due to increased proinflammatory cytokines releasing from abdominal adipose tissue. Eur J Gastroenterol Hepatol 2020;32(3):458 View Article PubMed/NCBI
  58. Metawea M, El Wazzan D, El-Shendidi A. Significance of altered anticoagulant proteins and D-dimer in cirrhotic portal vein thrombosis: relation to the degree of liver dysfunction. Clin Exp Hepatol 2022;8(3):233-242 View Article PubMed/NCBI
  59. Liu K, Chen J, Zhang K, Wang S, Li X. A Diagnostic Prediction Model of Acute Symptomatic Portal Vein Thrombosis. Ann Vasc Surg 2019;61:394-399 View Article PubMed/NCBI
  60. Yang J, Zhang X, Chen J, Hou X, Shi M, Yin L, et al. Development and validation of an integrated model for the diagnosis of liver cirrhosis with portal vein thrombosis combined with endoscopic characters and blood biochemistry data: a retrospective propensity score matching (PSM) cohort study. Ann Med 2025;57(1):2457521 View Article PubMed/NCBI
  61. Li L, Lu S, Cui C, Zeng X, Chen S. Risk factor analysis for portal vein thrombosis in 591 patients with liver cirrhosis. Fudan Univ J Med Sci 2017;44:288-293 View Article
  62. Zhang Y, Xu BY, Wang XB, Zheng X, Huang Y, Chen J, et al. Prevalence and Clinical Significance of Portal Vein Thrombosis in Patients With Cirrhosis and Acute Decompensation. Clin Gastroenterol Hepatol 2020;18(11):2564-2572.e1 View Article PubMed/NCBI
  63. Liu GH, Lei P, Liao CS, Li J, Long JW, Huan XS, et al. Establishment and verification a nomogram for predicting portal vein thrombosis presence among admitted cirrhotic patients. Front Med (Lausanne) 2022;9:1021899 View Article PubMed/NCBI
  64. Lin GS, Xu Q, Zhao SY, Zhang YX. Clinical features of liver cirrhosis complicated by portal vein thrombosis and related risk factors. Zhonghua Gan Zang Bing Za Zhi 2016;24(7):513-517 View Article PubMed/NCBI
  65. Zhao F, Ding J, Cui J, Zhu M, Zhao W. Platelet Activation is Upregulated in Cirrhotic Patients with Portal Vein Thrombosis. Thromb Haemost 2024;124(8):739-752 View Article PubMed/NCBI
  66. Lin WY, Lu X, Fan FJ, Hu Y. Predictive Effect of Mean Platelet Volume in Patients with Portal Vein Thrombosis: A Meta-analysis of Case-control Studies. Curr Med Sci 2018;38(4):575-581 View Article PubMed/NCBI
  67. Jiang S, Ai Y, Ni L, Wu L, Huang X, Chen S. Platelet-derived TGF-β1 is related to portal vein thrombosis in cirrhosis by promoting hypercoagulability and endothelial dysfunction. Front Cardiovasc Med 2022;9:938397 View Article PubMed/NCBI
  68. Quan X, Ye X, Qian S, Wei B, Tong H, Wang Z, et al. Portal vein thrombosis associates with high platelet-fibrin clot strength and platelet activation in decompensated cirrhosis: A retrospective study. Dig Liver Dis 2023;55(5):629-636 View Article PubMed/NCBI
  69. Song Z, Feng H, Yang C, Dai C. Prediction of the Factors Influencing the Shengjing Classification of Portal Vein Thrombosis after Splenectomy for Portal Hypertension in Cirrhosis: A Single-Center Retrospective Case-Control Study. Biomed Res Int 2020;2020:2396710 View Article PubMed/NCBI
  70. Walton BL, Byrnes JR, Wolberg AS. Fibrinogen, red blood cells, and factor XIII in venous thrombosis. J Thromb Haemost 2015;13(Suppl 1):S208-S215 View Article PubMed/NCBI
  71. Hugenholtz GC, Macrae F, Adelmeijer J, Dulfer S, Porte RJ, Lisman T, et al. Procoagulant changes in fibrin clot structure in patients with cirrhosis are associated with oxidative modifications of fibrinogen. J Thromb Haemost 2016;14(5):1054-1066 View Article PubMed/NCBI
  72. Suda T, Takatori H, Hayashi T, Kaji K, Nio K, Terashima T, et al. Plasma Antithrombin III Levels Can Be a Prognostic Factor in Liver Cirrhosis Patients with Portal Vein Thrombosis. Int J Mol Sci 2023;24(9):7732 View Article PubMed/NCBI
  73. Wu Z, Xiao Y, Qi Z, Guo T, Tong H, Wang Y. Effect of factor VIII and FVIII/PC ratio on portal vein thrombosis in liver cirrhosis: a systematic review and meta-analysis. BMC Gastroenterol 2024;24(1):320 View Article PubMed/NCBI
  74. Sacco M, Tardugno M, Lancellotti S, Ferretti A, Ponziani FR, Riccardi L, et al. ADAMTS-13/von Willebrand factor ratio: A prognostic biomarker for portal vein thrombosis in compensated cirrhosis. A prospective observational study. Dig Liver Dis 2022;54(12):1672-1680 View Article PubMed/NCBI
  75. Simonetto DA, Liu M, Kamath PS. Portal Hypertension and Related Complications: Diagnosis and Management. Mayo Clin Proc 2019;94(4):714-726 View Article PubMed/NCBI
  76. Elkrief L, Hernandez-Gea V, Senzolo M, Albillos A, Baiges A, Berzigotti A, et al. Portal vein thrombosis: diagnosis, management, and endpoints for future clinical studies. Lancet Gastroenterol Hepatol 2024;9(9):859-883 View Article PubMed/NCBI
  77. Prakash S, Bies J, Hassan M, Mares A, Didia SC. Portal vein thrombosis in cirrhosis: A literature review. Front Med (Lausanne) 2023;10:1134801 View Article PubMed/NCBI
  78. Turon F, Driever EG, Baiges A, Cerda E, García-Criado Á, Gilabert R, et al. Predicting portal thrombosis in cirrhosis: A prospective study of clinical, ultrasonographic and hemostatic factors. J Hepatol 2021;75(6):1367-1376 View Article PubMed/NCBI
  79. Zhong H, Lu S, Xu M, Liu N, Ye W, Yang Y. Predictive value of hepatic venous pressure gradient in cirrhotic portal vein thrombosis development. Clin Res Hepatol Gastroenterol 2024;48(10):102484 View Article PubMed/NCBI
  80. Kondili LA, Zanetto A, Quaranta MG, Ferrigno L, Panetta V, Calvaruso V, et al. Predicting de-novo portal vein thrombosis after HCV eradication: A long-term competing risk analysis in the ongoing PITER cohort. United European Gastroenterol J 2024;12(3):352-363 View Article PubMed/NCBI
  81. Arabpour E, Hatami B, Pasharavavesh L, Rabbani AH, Zarean Shahraki S, Amiri M, et al. Clinical characteristics and predictors of benign portal vein thrombosis in patients with liver cirrhosis: A retrospective single-center study. Medicine (Baltimore) 2024;103(38):e39823 View Article PubMed/NCBI
  82. Ak C, Adali G, Sayar S, Agackiran A, Kulali F, Kahraman R, et al. Portal vein thrombosis risk factors in liver transplant candidates. Hepatol Forum 2022;3(3):88-92 View Article PubMed/NCBI
  83. Lopez-Gomez M, Llop E, Puente A, Hernández Conde M, Ruiz P, Alvárez S, et al. Non-malignant portal vein thrombosis in a cohort of cirrhotic patients: Incidence and risk factors. Hepatol Res 2021;51(10):1064-1072 View Article PubMed/NCBI
  84. Hernández Conde M, Llop Herrera E, de la Revilla Negro J, Pons Renedo F, Fernández Puga N, Martínez Porras JL, et al. Prevalence and outcome of portal thrombosis in a cohort of cirrhotic patients undergoing liver transplantation. Rev Esp Enferm Dig 2016;108(11):716-720 View Article PubMed/NCBI
  85. Cagin YF, Bilgic Y, Berber İ, Yildirim O, Erdogan MA, Firat F, et al. The risk factors of portal vein thrombosis in patients with liver cirrhosis. Exp Ther Med 2019;17(4):3189-3194 View Article PubMed/NCBI
  86. Gîrleanu I, Trifan A, Cojocariu C, Sîngeap AM, Sfarti C, Stanciu C. The risk of thrombotic events in patients with liver cirrhosis. Rev Med Chir Soc Med Nat Iasi 2012;116(4):991-996 PubMed/NCBI
  87. Basili S, Carnevale R, Nocella C, Bartimoccia S, Raparelli V, Talerico G, et al. Serum Albumin Is Inversely Associated With Portal Vein Thrombosis in Cirrhosis. Hepatol Commun 2019;3(4):504-512 View Article PubMed/NCBI
  88. Pan J, Wang L, Gao F, An Y, Yin Y, Guo X, et al. Epidemiology of portal vein thrombosis in liver cirrhosis: A systematic review and meta-analysis. Eur J Intern Med 2022;104:21-32 View Article PubMed/NCBI
  89. Tang W, Wang Y, Zhao X, Wang X, Zhang T, Ou X, et al. Procoagulant imbalance aggravated with falling liver function reserve, but not associated with the presence of portal vein thrombosis in cirrhosis. Eur J Gastroenterol Hepatol 2015;27(6):672-678 View Article PubMed/NCBI
  90. Maruyama H, Okugawa H, Takahashi M, Yokosuka O. De novo portal vein thrombosis in virus-related cirrhosis: predictive factors and long-term outcomes. Am J Gastroenterol 2013;108(4):568-574 View Article PubMed/NCBI
  91. Noronha Ferreira C, Marinho RT, Cortez-Pinto H, Ferreira P, Dias MS, Vasconcelos M, et al. Incidence, predictive factors and clinical significance of development of portal vein thrombosis in cirrhosis: A prospective study. Liver Int 2019;39(8):1459-1467 View Article PubMed/NCBI
  92. Liu R, Lian H. Early Predictive Value of P-selectin and D-dimer for Portal Vein Thrombosis in Patients with Liver Cirrhosis. Chin J Thromb Hemost 2021;27:974-976 View Article
  93. Bertina RM, Koeleman BP, Koster T, Rosendaal FR, Dirven RJ, de Ronde H, et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994;369(6475):64-67 View Article PubMed/NCBI
  94. Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995;10(1):111-113 View Article PubMed/NCBI
  95. Ohlin AK, Norlund L, Marlar RA. Thrombomodulin gene variations and thromboembolic disease. Thromb Haemost 1997;78(1):396-400 PubMed/NCBI
  96. Chamouard P, Pencreach E, Maloisel F, Grunebaum L, Ardizzone JF, Meyer A, et al. Frequent factor II G20210A mutation in idiopathic portal vein thrombosis. Gastroenterology 1999;116(1):144-148 View Article PubMed/NCBI
  97. De Stefano V, Fiorini A, Rossi E, Za T, Chiusolo P, Sica S, et al. High prevalence of the JAK2 V617F mutation in patients with extrahepatic portal vein thrombosis. Hepatology 2007;45(3):831-832 View Article PubMed/NCBI
  98. D’Amico M, Pasta F, Pasta L. Thrombophilic genetic factors PAI-1 4G-4G and MTHFR 677TT as risk factors of alcohol, cryptogenic liver cirrhosis and portal vein thrombosis, in a Caucasian population. Gene 2015;568(1):85-88 View Article PubMed/NCBI
  99. Plompen EP, Valk PJ, Chu I, Darwish Murad SD, Plessier A, Turon F, et al. Somatic calreticulin mutations in patients with Budd-Chiari syndrome and portal vein thrombosis. Haematologica 2015;100(6):e226-e228 View Article PubMed/NCBI
  100. Zhang F, Gui Y, Lu Y, Liu D, Chen H, Qin X, et al. Novel SERPINC1 missense mutation (Cys462Tyr) causes disruption of the 279Cys-462Cys disulfide bond and leads to type I hereditary antithrombin deficiency. Clin Biochem 2020;85:38-42 View Article PubMed/NCBI
  101. Zou C, Li T, Long L, Liu L, Zhu J. Hereditary protein C deficiency with portal vein thrombosis in a Chinese male: A case report. Exp Ther Med 2022;24(6):751 View Article PubMed/NCBI
  102. Ye X, Mi X, Sun J, ShenTu Y, Fei Y, Tang D, et al. PROS1 variant c.1574C>T p.Ala525Val causes portal vein thrombosis with protein S deficiency. Clin Res Hepatol Gastroenterol 2023;47(6):102141 View Article PubMed/NCBI
  103. Amitrano L, Brancaccio V, Guardascione MA, Margaglione M, Iannaccone L, D’Andrea G, et al. Inherited coagulation disorders in cirrhotic patients with portal vein thrombosis. Hepatology 2000;31(2):345-348 View Article PubMed/NCBI
  104. Saugel B, Lee M, Feichtinger S, Hapfelmeier A, Schmid RM, Siveke JT. Thrombophilic factor analysis in cirrhotic patients with portal vein thrombosis. J Thromb Thrombolysis 2015;40(1):54-60 View Article PubMed/NCBI
  105. Ames PRJ, D’Andrea G, Arcaro A, Marottoli V, Iannaccone L, Maraglione M, et al. Liver Cirrhosis Patients Homozygous for MTHFR C677T Develop Portal Vein Thrombosis 8 Years Earlier Than Wild Type. Dig Dis Sci 2023;68(4):1332-1338 View Article PubMed/NCBI
  106. Key NS, Reiner AP. Genetic basis of ethnic disparities in VTE risk. Blood 2016;127(15):1844-1845 View Article PubMed/NCBI
  107. Ma SD, Wang J, Bezinover D, Kadry Z, Northup PG, Stine JG. Inherited thrombophilia and portal vein thrombosis in cirrhosis: A systematic review and meta-analysis. Res Pract Thromb Haemost 2019;3(4):658-667 View Article PubMed/NCBI
  108. Tang L, Lu X, Yu JM, Wang QY, Yang R, Guo T, et al. PROC c.574_576del polymorphism: a common genetic risk factor for venous thrombosis in the Chinese population. J Thromb Haemost 2012;10(10):2019-2026 View Article PubMed/NCBI
  109. Caprini JA. Thrombosis risk assessment as a guide to quality patient care. Dis Mon 2005;51(2-3):70-78 View Article PubMed/NCBI
  110. Qi X, Chen H, Han G. Effect of antithrombin, protein C and protein S on portal vein thrombosis in liver cirrhosis: a meta-analysis. Am J Med Sci 2013;346(1):38-44 View Article PubMed/NCBI
  111. Hepatobiliary Disease Study Group, Chinese Society of Gastroenterology, Chinese Medical Association. Consensus for management of portal vein thrombosis in liver cirrhosis (2020, Shanghai). J Dig Dis 2021;22(4):176-186 View Article PubMed/NCBI
  112. Li J, Wang Q, Yang M, Sun X. Metabolic Disorders and Risk of Portal Vein Thrombosis in Liver Cirrhosis: A Systematic Review and Meta-Analysis. Turk J Gastroenterol 2022;33(7):541-553 View Article PubMed/NCBI
  113. Liao Z, Wang Z, Su C, Pei Y, Li W, Liu J. Long term prophylactic anticoagulation for portal vein thrombosis after splenectomy: A systematic review and meta-analysis. PLoS One 2023;18(8):e0290164 View Article PubMed/NCBI
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Yang Z, Zhao Y, Chen H, Zhang H, Tan M, Li X, et al. Portal Vein Thrombosis in Liver Cirrhosis: A Review of Risk Factors and Predictive Indicators. J Clin Transl Hepatol. Published online: Jul 29, 2025. doi: 10.14218/JCTH.2025.00124.
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Article History
Received Revised Accepted Published
March 13, 2025 June 17, 2025 July 3, 2025 July 29, 2025
DOI http://dx.doi.org/10.14218/JCTH.2025.00124
  • Journal of Clinical and Translational Hepatology
  • pISSN 2225-0719
  • eISSN 2310-8819
  • © 2025 Xia & He Publishing Inc.
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Portal Vein Thrombosis in Liver Cirrhosis: A Review of Risk Factors and Predictive Indicators

Zhicheng Yang, Yongle Zhao, Honglin Chen, Han Zhang, Maoting Tan, Xianliu Li, Lingling Tao, Hongyun Zhao
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