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Hepatology
Von Willebrand factor levels predict clinical outcome in patients with cirrhosis and portal hypertension
  1. Vincenzo La Mura1,2,
  2. Juan Carlos Reverter3,
  3. Alexandra Flores-Arroyo1,2,
  4. Sebastián Raffa1,2,
  5. Enric Reverter1,2,
  6. Susana Seijo1,2,
  7. Juan G Abraldes1,2,
  8. Jaime Bosch1,2,
  9. Juan Carlos García-Pagán1,2
  1. 1Hepatic Haemodynamic Laboratory, Liver Unit. Hospital Clínic-Institut de investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Spain
  2. 2Centro de Investigación Biomédica en red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
  3. 3Hemotherapy and Hemostasis Department, Hospital Clínic, IDIBAPS, University of Barcelona, Spain
  1. Correspondence to Dr Juan Carlos García-Pagán, Calle Villarroel 170, Barcelona 08036, Spain; jcgarcia{at}clinic.ub.es

Abstract

Background and aims Endothelial dysfunction is a major determinant of the increased hepatic vascular tone of cirrhotic livers. Von Willebrand factor (vWF), P-selectin and 8-iso-PGF2α (isoprostanes), surrogate markers of endothelial dysfunction, are increased in patients with cirrhosis. This study was aimed at exploring in patients with cirrhosis and portal hypertension the relation of these endothelial factors with systemic and hepatic haemodynamics and their possible clinical prognostic value.

Methods 42 consecutive patients with cirrhosis and portal hypertension had measurement of the hepatic venous pressure gradient (HVPG), cardiopulmonary pressures and vWF, P-selectin and isoprostane levels in blood samples from hepatic and peripheral veins. Patients were followed up to 2 years, death or liver transplantation and any clinical event were recorded.

Results vWF, P-selectin and isoprostanes were increased in patients with cirrhosis compared with controls (p<0.001). vWF levels significantly correlated with HVPG, Child–Pugh score and MELD. Cox model analysis disclosed an independent indirect association of peripheral vWF with survival free of portal hypertension-related events and of transplantation. The vWF cut-off value of 216 U/dl (Youden index) disclosed two different populations of patients with cirrhosis with a highly different probability of survival free of portal hypertension-related events and transplantation (87% vs 22%, p=0.001). The prognostic role of vWF persisted after adjusting for parameters of liver dysfunction and for HVPG.

Conclusions In patients with cirrhosis and portal hypertension vWF levels correlate with liver function and HVPG and independently predict clinical outcome.

  • Cirrhosis
  • endothelial dysfunction
  • haemodynamics in cirrhosis
  • hepatic haemodynamics
  • isoprostanes
  • nitric oxide
  • prognosis
  • P-selectin

https://doi.org/10.1136/gut.2010.235689

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    Significance of this study

    What is already known about this subject?

    • Endothelial dysfunction is an early key event in many vascular diseases and is considered a major determinant of the increased hepatic vascular tone of cirrhotic livers.

    • A subtle hypercoagulable state has recently been evidenced in advanced chronic liver diseases.

    • Peripheral levels of vWF, P-selectin and isoprostranes, surrogate markers of endothelial dysfunction, are increased in patients with cirrhosis.

    What are the new findings?

    • In patients with cirrhosis and portal hypertension peripheral and hepatic levels of vWF correlate with liver function and HVPG.

    • High peripheral levels of vWF predict the prognosis of patients with cirrhosis, independently of liver function and portal hypertension.

    • The value of vWF of 216 U/dl is a possible cut-off to discriminate two different populations of patients with cirrhosis with a highly different probability of survival free of portal hypertension-related events and of transplantation.

    How might it impact on clinical practice in the foreseeable future?

    • vWF is a promising endothelial-derived molecule to be taken into account to improve prognostic models in patients with cirrhosis and portal hypertension.

    Portal hypertension is a serious consequence of cirrhosis that may result in life-threatening complications with increased morbidity and mortality.1 In cirrhotic livers, increased resistance to portal blood flow is the primary factor in the pathophysiology of portal hypertension and is caused by structural abnormalities in the hepatic vascular architecture and an increased hepatic vascular tone.2

    The endothelium plays a pivotal role modulating vascular tone and inflammatory processes via the release of nitric oxide, which has vasodilatory, anti-inflammatory and antithrombotic properties. Endothelial dysfunction is an early key event in many vascular diseases and is considered a major determinant of the increased hepatic vascular tone of cirrhotic livers.3 4

    Von Willebrand factor (vWF), P-selectin and isoprostranes have been used as markers of endothelial function.5–7 vWF is a large adhesive protein released by activated endothelial cells and therefore represents an indicator of endothelial cell activation,8 which is easy to measure.9 In patients with angina pectoris or acute myocardial infarction, vWF levels are independent predictors of subsequent acute myocardial infarction and mortality, respectively.5 Levels of vWF are increased in patients with cirrhosis and correlate with the severity of liver disease,10 with the levels of endotoxaemia11 and of nitric oxide.12

    P-selectin is a cell adhesion receptor expressed mainly on the surface of platelets and endothelial cells and part of P-selectin is shed into the circulation. In healthy individuals, high levels of soluble P-selectin have been shown to predict clinical cardiovascular events13 and to correlate with subclinical atherosclerosis.14 15 P-selectin levels are increased in patients with cirrhosis, mainly in those with severe liver dysfunction.16

    Isoprostanes are prostaglandin isomers generated by oxygen free radical-mediated peroxidation of membrane phospholipids.17 They have been used clinically and experimentally as markers of oxidative stress.18 19 Isoprostanes are increased in peripheral and portal venous blood of patients with cirrhosis.20

    The main aim of this study was to explore in patients with cirrhosis and portal hypertension the relation of vWF, P-selectin and isoprostane levels with systemic and splanchnic haemodynamics. The secondary aim was to examine the possible prognostic value of those markers correlating with haemodynamics with regard to clinical outcome.

    Patients and methods

    Study cohort and follow-up

    Consecutive patients with cirrhosis undergoing a hepatic and systemic haemodynamic study for the evaluation of portal hypertension were enrolled in the study. All gave a specific written informed consent. The study protocol was approved by the ethics committee of Hospital Clínic, and was conducted according to the Declaration of Helsinki (last reviewed in Seoul, October 2008).

    Liver cirrhosis was diagnosed by clinical, biochemical, ultrasonographic and/or histological criteria. All patients had severe portal hypertension, demonstrated by a hepatic venous pressure gradient (HVPG) of 12 mm Hg or greater. Exclusion criteria were: gastrointestinal bleeding; infection or hepatorenal syndrome within 1 month; prothrombin rate less than 40% and bilirubin greater than 5 mg/dl; pregnancy; portal vein thrombosis; cardiac, renal or respiratory failure; previous surgical or transjugular intrahepatic portosystemic shunt; hepatocellular carcinoma; cholestatic liver disease and treatment with vasoactive drugs (including β-blockers), statins, aspirin or other non-steroidal anti-inflammatory drugs, antibiotics and antioxidants in the previous 2 weeks.

    After discharge all patients were followed in the outpatient clinic at 1, 3 and 6 months and every 6 months thereafter or whenever a clinical event occurred during follow-up. Medical history, physical examination, biochemistry, haematological tests, abdominal ultrasound and alcohol consumption were recorded every 6 months. Follow-up data were retrospectively collected for up to 2 years, death, liver transplantation or if a derivative procedure was performed (transjugular intrahepatic portosystemic shunt or surgery). We registered the following clinical events: (1) portal hypertension-related events that included first variceal bleeding or rebleeding; de novo ascites or worsening ascites requiring hospitalisation, hepatic encephalopathy requiring hospitalisation, hepatorenal syndrome and spontaneous bacterial peritonitis; (2) death and (3) liver transplantation. In addition, we also registered any infective episode other than spontaneous bacterial peritonitis. The combined endpoint (whatever first) of the development of portal hypertension complications, death or liver transplantation was the main variable used for survival analysis.

    Haemodynamic study

    After fasting overnight, the patients were transferred to the hepatic haemodynamic laboratory. Under local anaesthesia, an 8 F venous catheter introducer (Axcess; Maxim Medical, Athens, Texas, USA) was placed in the right jugular vein under ultrasonographic guidance (SonoSite Inc, Bothell, Washington, USA) using the Seldinger technique. Under fluoroscopic control, a Swan–Ganz catheter (Edwars Laboratory, Los Angeles, California, USA) was advanced into the pulmonary artery for the measurement of cardiopulmonary pressures and cardiac output by thermal dilution. A 7 F balloon-tipped catheter (Edwars Laboratory) was also advanced into the main right hepatic vein to measure the wedged hepatic venous pressure and free hepatic venous pressure. Mean arterial pressure (MAP) was measured every 5 min by an external automatic sphygmomanometer (Marquette Electronics, Milwaukee, Wisconsin, USA). Heart rate was derived from continuous electrocardiogram monitoring.

    All measurements were performed in triplicate in each study period, and permanent tracings were obtained on a multichannel recorder (Marquette Electronics). Portal pressure was estimated from the HVPG: the difference between wedged hepatic venous pressure and free hepatic venous pressure. The cardiac index was calculated as cardiac output/body surface (l/min/m2) and the systemic vascular resistance index was calculated as (MAP–right atrial pressure)×80/IC (dyne s/cm5/m2) (MAP and right atrial pressure, mm Hg).

    Biochemical analysis

    Blood samples from the hepatic and peripheral vein were collected into a citrate-containing tube (0.129 M, 3.8%; Vacutainer system, Becton Dickinson, San Jose, California, USA) during haemodynamic measurement. After centrifugation at 3.000g for 20 min at 4°C plasma was aliquoted and stored at −80°C for subsequent analysis. vWF (vWF:Ag), soluble P-selectin, isoprostanes (8-iso-PGF2α) were evaluated by an ELISA system, as previously described.21–24 Eighteen healthy controls, matched for sex and age, were used as controls for the peripheral levels of vWF, P-selectin and total isoprostanes determination.

    Statistics

    Statistical analysis was performed using SPSS 16.0 statistical package. All results were expressed as mean±SD values. Comparisons within each group were performed with the Student's t test for paired data and comparisons between groups with the Student's t test for unpaired data; the Wilcoxon test was used when appropriate. Correlation was performed by means of Pearson's coefficient. Statistical significance was established at p<0.05.

    The adjusted influence of each marker on the risk of developing the clinical endpoints was estimated by a multivariable Cox analysis introducing the MELD score (as an objective test of liver function) and the HVPG (as an objective marker of the degree of portal hypertension) as covariates. The contribution of each variable to the risk of reaching the endpoint was estimated by the relative hazard with its 95% CI. Receiver operating characteristic curve analysis was used to test the accuracy of continuous variables independently associated with prognosis.

    The best cut-off level of vWF to predict the clinical outcome was selected by using the Youden index, a well characterised objective method that maximised the sum of sensitivity and specificity.25 26 The discriminative ability of this cut-off to predict the prognosis was analysed by Kaplan–Meier curves and compared with the log-rank test.

    Results

    Forty-two consecutive patients with cirrhosis were included in the study. Their clinical, endoscopic and haemodynamic characteristics are reported in table 1.

    View this table:
    Table 1

    Clinical, endoscopic and haemodynamic characteristics of patients included in the study

    Relationship between endothelial markers and clinical and haemodynamic parameters

    In patients with cirrhosis peripheral levels of vWF were significantly increased (vWF 222±17 U/dl vs 104±13 U/dl in healthy controls, p<0.001) (figure 1). Levels of vWF at the hepatic vein were slightly higher than those at the peripheral vein (225±16 U/dl vs 222±17 U/dl, p=0.074, paired sample t-test). Peripheral levels of vWF correlated with the Child–Pugh score (r=0.43, p=0.018) and MELD (r=0.34, p=0.032). The same was observed for hepatic levels of vWF (data not shown).

    Figure 1
    Figure 1

    Box-plot of peripheral levels of von Willebrand factor (vWF), P-selectin and 8-iso-PGF2α (isoprostanes). The boxes correspond to median value and the interquartile range. All the markers of endothelial dysfunction were significantly higher in patients with cirrhosis than in controls. *Isoprostanes were measured in 22 patients.

    A positive linear correlation was found between peripheral levels of vWF and HVPG (r=0.47, p<0.001) (figure 2) and heart rate. Similar results were observed for hepatic levels of vWF.

    Figure 2
    Figure 2

    Linear correlation between hepatic venous pressure gradient (HVPG) (mm Hg) and von Willebrand factor (vWF) (U/dl).

    Peripheral levels of P-selectin were significantly increased in patients with cirrhosis in comparison with controls (P-selectin 54.6±22.0 ng/ml vs 30.9±10.9 ng/ml, p<0.001) (figure 1). Peripheral levels of P-selectin were not significantly higher than hepatic vein levels (63.9±54.8 ng/ml vs 54.6±22.0 ng/ml, respectively; p=0.140). Peripheral P-selectin levels showed a significant positive correlation with heart rate. In addition, peripheral P-selectin levels correlated with platelet and leucocyte counts (r=0.42, p=0.019; r=0.44, p=0.017, respectively). Similar results were observed with hepatic P-selectin levels (data not shown).

    In a subgroup of 22 patients, peripheral and hepatic levels of isoprostanes were measured. Peripheral isoprostane levels were significantly increased in patients with cirrhosis in comparison with controls (12.3±12.2 pg/ml vs 0.8±0.6 pg/ml in controls; p<0.001) (figure 1). Peripheral levels of isoprostanes were slightly higher than those at the hepatic vein (12.3±12.2 pg/ml vs 8.0±6.5, respectively; p=0.077).

    Isoprostane levels did not correlate with any clinical haemodynamic parameter except with heart rate (r=0.51, p=0.032).

    Endothelial markers: relationship with clinical outcome

    The median follow-up was 23.6 months (range 1.2–24.0 months). In summary, during follow-up, 19 patients died, were transplanted or had a portal hypertension-related event. The remaining 23 patients did not develop any clinical event (for more details see table 2). The Cox model analysis disclosed an independent association of peripheral vWF (1.21, 95% CI 1.03 to 1.42, p=0.022) and MELD score (1.05, 95% CI 1.01 to 1.08, p=0.016) with survival free of portal hypertension-related events and transplantation (n=19 events) (table 3). The analysis of the accuracy of these two variables independently associated with the prognosis did not disclose any significant difference based on the receiver operating characteristic curve (area under the curve for MELD 0.739, 95% CI 0.585 to 0.893 and area under the curve for vWF 0.740, 95% CI 0.580 to 0.900). To explore further the existence of a potential cut-off of vWF useful to discriminate patients for the risk of developing this combined endpoint, the cohort was split according to the cut-off of 216 U/dl disclosed by the Youden index as the value of vWF that maximised the sum of sensitivity (84%) and specificity (61%). Patients with peripheral levels of vWF below this value had a significantly higher probability of survival free of portal hypertension-related complications and transplantation than patients with vWF above 216 U/dl (87% vs 22%, p=0.001) (figure 3A). The additive prognostic value of vWF on MELD is further shown in figure 4.

    View this table:
    Table 2

    Clinical events during follow-up

    View this table:
    Table 3

    Univariable and multivariable analysis of factors related to survival free of portal hypertension complication and transplantation

    Figure 3
    Figure 3

    (A) Incidence of portal hypertension-related events and transplantation in patients with peripheral von Willebrand factor (vWF) levels above and below the value corresponding to the best Youden index (216 UI/dl). (B) Transplantation-free survival (11 events) in patients with cirrhosis and vWF levels above and below 216 UI/dl. *HR indicating the risk of the event adjusting for portal hypertension and liver function.

    Figure 4
    Figure 4

    Patients with high von Willebrand factor (vWF) had a poor outcome independently of the MELD.

    Patients with vWF below 216 U/dl also had a better transplantation-free survival than those with vWF above 216 U/dl (p=0.001) (figure 3B). No multivariable analysis was specifically conducted for transplantation-free survival due to the low number of events.

    There was no evidence of an association between P-selectin or isoprostanes and clinical events during follow-up.

    Discussion

    Endothelial dysfunction is an early key event in vascular disorders, and its presence has been associated with poor prognosis. In cirrhosis, endothelial dysfunction in the hepatic vascular bed is considered a major determinant of the increased vascular tone of cirrhotic livers and therefore of the development of portal hypertension.2 4 Our study clearly shows that in patients with cirrhosis the markers of endothelial dysfunction—vWF, P-selectin and isoprostanes—are significantly increased. This finding has previously been reported;10 16 20 however, this is the first study exploring the association between increased levels of these markers and systemic and hepatic haemodynamic disturbances as well as their possible value in predicting prognosis.

    The most interesting results of our study are related to vWF. Circulating levels of vWF had a significant direct correlation with HVPG. Considering vWF as a marker of endothelial dysfunction, our findings support the previous recognised role of endothelial dysfunction in the pathogenesis of increased hepatic resistance to portal blood flow in patients with cirrhosis. The fact that the correlation between vWF and HVPG was not strong is not unexpected and probably reflects the fact that endothelial dysfunction is not the only determinant of portal hypertension. In addition, and clinically more relevant, a marked elevation of vWF levels was associated with a lower probability of remaining alive without developing portal hypertension-related complications or requiring liver transplantation. Remarkably, multivariable analysis disclosed an association of vWF with prognosis that was independent of that of HVPG or the degree of liver failure. Therefore, in patients with a similar degree of liver failure and portal hypertension, those with higher vWF levels have a worse prognosis. This may suggest that the factors leading to increased vWF might contribute to disease progression. It has recently been suggested that propranolol may influence vWF levels.27 However, when vWF was measured at baseline conditions all patients were free of vasoactive treatment including β-blockers.

    The mechanism as to how vWF is involved in complication-free survival is beyond the scope of this paper. However, several mechanisms can be speculated. vWF is a procoagulant factor that has a dual effect: it participates in primary haemostasis through formation of the vWF–platelet–collagen plug and guarantees a phospholipid platform that promotes the generation of the thrombin burst.28 It has recently been demonstrated that patients with cirrhosis exhibit a hypercoagulable state.29 30 It is likely that increased levels of vWF in patients with cirrhosis might contribute to this hypercoagulability. In that regard it has been suggested that microthrombotic events within the liver vasculature may contribute to the progression to decompensation through the development of progressive hepatic extinction lesions.31 It is remarkable that preliminary data from a randomised controlled trial suggested that long-term anticoagulation may prevent the development of clinical events in patients with compensated cirrhosis.32 Therefore, the association of vWF with poor prognosis may be partly due to the fact that it might reflect a subtle hypercoagulable status in these patients.

    Several mechanisms have been proposed to explain the increase of vWF in cirrhosis, including endothelial cell damage as a result of bacterial-derived products promoting endothelial secretion of vWF,11 33 expanded endothelial surface due to collateralisation and angiogenesis,11 33 and reduced clearance of vWF, possibly due to the reduced levels of the cleaving protease ADAMTS13.34 In our study, hepatic venous levels of vWF were slightly higher, although not reaching statistical significance, than those in the peripheral vein, suggesting a hepatosplanchnic release of vWF. This, with the fact that mRNA vWF expression has been found to be enhanced in the endothelium of cirrhotic livers,30 suggests that the liver endothelium may be a source of increased levels of vWF in patients with cirrhosis, which is consistent with the well demonstrated hepatic endothelial dysfunction in cirrhosis.3 4

    P-selectin and isoprostanes were also found to be increased in patients with cirrhosis. However, these parameters were poorly or not correlated with HVPG and were not associated with prognosis. A recent experimental observation evidenced a key role for vWF, but not for P-selectin, in microvascular thrombosis induced by lipopolysaccharide, remarking that probably these endothelial factors play different physiological roles in the haemostasis process.35 On the other hand, it has been suggested that urinary isoprostanes may be a more reliable estimate of isoprostane production than its circulating levels.19 Unfortunately, urinary isoprostanes were not measured in our study. Therefore, we can not completely exclude the possibility that urinary isoprostanes may correlate with prognosis in patients with advanced liver failure, especially in those with impaired renal function.

    Our results strongly indicate that vWF is a promising endothelial-derived molecule to be taken into account in prognostic models in patients with cirrhosis and portal hypertension, although new studies are needed to confirm the prognostic value of vWF. The causative role of altered haemostasis as a further consequence of endothelial damage in cirrhosis is a suggestive hypothesis that should be explored by adequately designed human studies.

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    Footnotes

    • Competing interests None.

    • Patient consent Obtained.

    • Ethics approval This study was conducted with the approval of the Ethics Committee of Hospital Clínic.

    • Provenance and peer review Not commissioned; externally peer reviewed.

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