Portal vein thrombosis: A predictable milestone in cirrhosis?
Authors: Juan Carlos Garcia-Pagan, Dominique-Charles Valla
Journal: Journal of Hepatology (2009)

Thrombotic risk factors in patients with liver cirrhosis: Correlation with MELD scoring system and portal vein thrombosis developmentJournal of HepatologyVol. 51Issue 4PreviewPrognostic scores currently used in cirrhotic patients do not include thrombotic risk factors (TRFs). Predicting factors of portal vein thrombosis (PVT) development are still unknown. We wanted to describe TRFs as a function of liver disease severity using the MELD score and assess the role of local and systemic TRFs as predictors of PVT development in cirrhotic patients. Full-Text PDF Development of portal vein thrombosis (PVT) is a significant milestone in the natural history of cirrhosis. It is associated with worsening liver function, ascites, and the occurrence of gastroesophageal variceal bleeding. However, previous studies have been cross-sectional in design, and therefore have not been able to address whether this association is causal (i.e. PVT actually causes decompensation) or whether the development of PVT is only a further consequence of advanced liver disease. On the other hand, it is clear that PVT increases morbidity and mortality associated with liver transplant and may even contraindicate it [1Yerdel M.A. Gunson B. Mirza D. Karayalcin K. Olliff S. Buckels J. et al.Portal vein thrombosis in adults undergoing liver transplantation: risk factors, screening, management, and outcome.Transplantation. 2000; 69: 1873-1881Crossref PubMed Scopus (549) Google Scholar, 2Nonami T. Yokoyama I. Iwatsuki S. Starzl T.E. The incidence of portal vein thrombosis at liver transplantation.Hepatology. 1992; 16: 1195-1198Crossref PubMed Scopus (229) Google Scholar]. Thus, taken together, these data suggest that PVT is a major index of poor prognosis in patients with cirrhosis. Numerous investigators have studied the prevalence of non-tumoral PVT, and the mechanisms and/or factors predicting its occurrence, in patients with cirrhosis [1Yerdel M.A. Gunson B. Mirza D. Karayalcin K. Olliff S. Buckels J. et al.Portal vein thrombosis in adults undergoing liver transplantation: risk factors, screening, management, and outcome.Transplantation. 2000; 69: 1873-1881Crossref PubMed Scopus (549) Google Scholar, 2Nonami T. Yokoyama I. Iwatsuki S. Starzl T.E. The incidence of portal vein thrombosis at liver transplantation.Hepatology. 1992; 16: 1195-1198Crossref PubMed Scopus (229) Google Scholar, 3Amitrano L. Guardascione M.A. Brancaccio V. Margaglione M. Manguso F. Iannaccone L. et al.Risk factors and clinical presentation of portal vein thrombosis in patients with liver cirrhosis.J Hepatol. 2004; 40: 736-741Abstract Full Text Full Text PDF PubMed Scopus (452) Google Scholar, 4Amitrano L. Brancaccio V. Guardascione M.A. Margaglione M. Sacco M. Martino R. et al.Portal vein thrombosis after variceal endoscopic sclerotherapy in cirrhotic patients: role of genetic thrombophilia.Endoscopy. 2002; 34: 535-538Crossref PubMed Scopus (81) Google Scholar, 5Amitrano L. Brancaccio V. Guardascione M.A. Margaglione M. Iannaccone L. D'Andrea G. et al.Inherited coagulation disorders in cirrhotic patients with portal vein thrombosis.Hepatology. 2000; 31: 345-348Crossref PubMed Scopus (226) Google Scholar, 6Francoz C. Belghiti J. Vilgrain V. Sommacale D. Paradis V. Condat B. et al.Splanchnic vein thrombosis in candidates for liver transplantation: usefulness of screening and anticoagulation.Gut. 2005; 54: 691-697Crossref PubMed Scopus (440) Google Scholar, 7Erkan O. Bozdayi A.M. Disibeyaz S. Oguz D. Ozcan M. Bahar K. et al.Thrombophilic gene mutations in cirrhotic patients with portal vein thrombosis.Eur J Gastroenterol Hepatol. 2005; 17: 339-343Crossref PubMed Scopus (66) Google Scholar, 8Mangia A. Villani M.R. Cappucci G. Santoro R. Ricciardi R. Facciorusso D. et al.Causes of portal venous thrombosis in cirrhotic patients: the role of genetic and acquired factors.Eur J Gastroenterol Hepatol. 2005; 17: 745-751Crossref PubMed Scopus (76) Google Scholar]. The reported prevalence of non-tumoral portal vein thrombosis in cirrhosis was highly variable ranging from 0.6 to 26%, probably due to the different groups of cirrhotic patients studied and the different diagnostic procedures used [1Yerdel M.A. Gunson B. Mirza D. Karayalcin K. Olliff S. Buckels J. et al.Portal vein thrombosis in adults undergoing liver transplantation: risk factors, screening, management, and outcome.Transplantation. 2000; 69: 1873-1881Crossref PubMed Scopus (549) Google Scholar, 2Nonami T. Yokoyama I. Iwatsuki S. Starzl T.E. The incidence of portal vein thrombosis at liver transplantation.Hepatology. 1992; 16: 1195-1198Crossref PubMed Scopus (229) Google Scholar, 3Amitrano L. Guardascione M.A. Brancaccio V. Margaglione M. Manguso F. Iannaccone L. et al.Risk factors and clinical presentation of portal vein thrombosis in patients with liver cirrhosis.J Hepatol. 2004; 40: 736-741Abstract Full Text Full Text PDF PubMed Scopus (452) Google Scholar, 4Amitrano L. Brancaccio V. Guardascione M.A. Margaglione M. Sacco M. Martino R. et al.Portal vein thrombosis after variceal endoscopic sclerotherapy in cirrhotic patients: role of genetic thrombophilia.Endoscopy. 2002; 34: 535-538Crossref PubMed Scopus (81) Google Scholar, 5Amitrano L. Brancaccio V. Guardascione M.A. Margaglione M. Iannaccone L. D'Andrea G. et al.Inherited coagulation disorders in cirrhotic patients with portal vein thrombosis.Hepatology. 2000; 31: 345-348Crossref PubMed Scopus (226) Google Scholar, 6Francoz C. Belghiti J. Vilgrain V. Sommacale D. Paradis V. Condat B. et al.Splanchnic vein thrombosis in candidates for liver transplantation: usefulness of screening and anticoagulation.Gut. 2005; 54: 691-697Crossref PubMed Scopus (440) Google Scholar]. The study by Zocco et al. in the present issue of the Journal further addresses this issue in a series of 73 prospectively followed up, consecutive patients with cirrhosis, in whom PVT was initially excluded with US-Doppler [[9]Zocco M.A. Di Stasio E. De Cristofaro R. Novi M. Ainora M.E. Ponziani F. et al.Thrombotic risk factors in patients with liver cirrhosis: Correlation with MELD scoring system and portal vein thrombosis development.J Hepatol. 2009; 51: 682-689Abstract Full Text Full Text PDF PubMed Scopus (379) Google Scholar]. The incidence of de novo thrombosis within one year was 16%, a figure comparable to that reported by Amitrano et al. [[4]Amitrano L. Brancaccio V. Guardascione M.A. Margaglione M. Sacco M. Martino R. et al.Portal vein thrombosis after variceal endoscopic sclerotherapy in cirrhotic patients: role of genetic thrombophilia.Endoscopy. 2002; 34: 535-538Crossref PubMed Scopus (81) Google Scholar] in a group of cirrhotic patients followed up prospectively during a similar period of time. The development of PVT was more frequent in patients with advanced liver disease, but a low portal blood flow velocity was the only factor independently predicting the occurrence of PVT during follow-up [[9]Zocco M.A. Di Stasio E. De Cristofaro R. Novi M. Ainora M.E. Ponziani F. et al.Thrombotic risk factors in patients with liver cirrhosis: Correlation with MELD scoring system and portal vein thrombosis development.J Hepatol. 2009; 51: 682-689Abstract Full Text Full Text PDF PubMed Scopus (379) Google Scholar]. In previous studies of patients with cirrhosis, male sex, previous surgery or interventional treatment of portal hypertension, previous variceal bleeding, low platelet count and advanced liver failure have shown to be associated with an increased risk for developing non-tumoral PVT [1Yerdel M.A. Gunson B. Mirza D. Karayalcin K. Olliff S. Buckels J. et al.Portal vein thrombosis in adults undergoing liver transplantation: risk factors, screening, management, and outcome.Transplantation. 2000; 69: 1873-1881Crossref PubMed Scopus (549) Google Scholar, 3Amitrano L. Guardascione M.A. Brancaccio V. Margaglione M. Manguso F. Iannaccone L. et al.Risk factors and clinical presentation of portal vein thrombosis in patients with liver cirrhosis.J Hepatol. 2004; 40: 736-741Abstract Full Text Full Text PDF PubMed Scopus (452) Google Scholar, 4Amitrano L. Brancaccio V. Guardascione M.A. Margaglione M. Sacco M. Martino R. et al.Portal vein thrombosis after variceal endoscopic sclerotherapy in cirrhotic patients: role of genetic thrombophilia.Endoscopy. 2002; 34: 535-538Crossref PubMed Scopus (81) Google Scholar, 6Francoz C. Belghiti J. Vilgrain V. Sommacale D. Paradis V. Condat B. et al.Splanchnic vein thrombosis in candidates for liver transplantation: usefulness of screening and anticoagulation.Gut. 2005; 54: 691-697Crossref PubMed Scopus (440) Google Scholar]. All of these findings have arisen from cross-sectional studies comparing cirrhotic patients with or without PVT. In the prospective study by Zocco et al., patients with a portal blood flow velocity less than 15 cm/s at initial US-Doppler evaluation had a higher incidence of PVT (47.8%) than those with a portal blood flow velocity >15 cm/s (2%) [[9]Zocco M.A. Di Stasio E. De Cristofaro R. Novi M. Ainora M.E. Ponziani F. et al.Thrombotic risk factors in patients with liver cirrhosis: Correlation with MELD scoring system and portal vein thrombosis development.J Hepatol. 2009; 51: 682-689Abstract Full Text Full Text PDF PubMed Scopus (379) Google Scholar]. It must be stated, when considering this cut-off value, that in the study by Zocco et al., portal blood velocity was reported as the averaged maximum value. However, in other studies portal blood velocity was shown as the mean and not the maximum value [10Siringo S. Bolondi L. Gaiani S. Sofia S. Zironi G. Rigamonti A. et al.Timing of the first variceal hemorrhage in cirrhotic patients: prospective evaluation of Doppler flowmetry, endoscopy and clinical parameters.Hepatology. 1994; 20: 66-73Crossref PubMed Scopus (67) Google Scholar, 11Merkel C. Sacerdoti D. Bolognesi M. Bombonato G. Gatta A. Doppler sonography and hepatic vein catheterization in portal hypertension: assessment of agreement in evaluating severity and response to treatment.J Hepatol. 1998; 28: 622-630Abstract Full Text PDF PubMed Scopus (58) Google Scholar, 12Bolognesi M. Sacerdoti D. Mescoli C. Bombonato G. Cillo U. Merenda R. et al.Different hemodynamic patterns of alcoholic and viral endstage cirrhosis: analysis of explanted liver weight, degree of fibrosis and splanchnic Doppler parameters.Scand J Gastroenterol. 2007; 42: 256-262Crossref PubMed Scopus (31) Google Scholar]. Several aspects in the design of the study under discussion must be considered. Were patients included in the study in fact unselected? Therefore, can these data be extrapolated to the general population of patients with cirrhosis? Is a reduction in portal blood flow velocity the best parameter to select cirrhotic patients at high risk of developing PVT, or can other inherited or acquired factors substitute or improve its prognostic capacity? The recruitment of a representative sample of patients who do not have the outcome of interest at the time of the initial examination is an issue of particular importance when analyzing prognostic risk factors for this outcome [[13]Guyatt G. Determining prognosis and creating clinical decision rules.in: Haynes B. Sackett D.L. Guyatt G. Tulliez M. Clinical epidemiology. 3rd ed. Lippincott Williams & Wilkins, 2006: 323-355Google Scholar]. Hence, in the study by Zocco et al., patients with reversed portal blood flow and with known coagulation disorders other than liver disease, such as Factor V Leiden mutation or the mutation 20210 of the prothrombin gene, were not enrolled [[9]Zocco M.A. Di Stasio E. De Cristofaro R. Novi M. Ainora M.E. Ponziani F. et al.Thrombotic risk factors in patients with liver cirrhosis: Correlation with MELD scoring system and portal vein thrombosis development.J Hepatol. 2009; 51: 682-689Abstract Full Text Full Text PDF PubMed Scopus (379) Google Scholar]. Exclusion of these patients may have influenced the results of the study. Indeed, a study in a large series of patients with cirrhosis found a prevalence of reversed flow in the portal venous system of 8.3% [[14]Gaiani S. Bolondi L. Li B.S. Zironi G. Siringo S. Barbara L. Prevalence of spontaneous hepatofugal portal flow in liver cirrhosis. Clinical and endoscopic correlation in 228 patients.Gastroenterology. 1991; 100: 160-167PubMed Google Scholar]. This prevalence increased to 12.5% in Child B, and 15% in Child C, patients. Remarkably, 57% of those patients with reversed flow in the portal vein trunk had partial PVT [[14]Gaiani S. Bolondi L. Li B.S. Zironi G. Siringo S. Barbara L. Prevalence of spontaneous hepatofugal portal flow in liver cirrhosis. Clinical and endoscopic correlation in 228 patients.Gastroenterology. 1991; 100: 160-167PubMed Google Scholar]. Similarly, the presence of the 20210 G-A prothrombin gene mutation was found to be associated with an increased risk of PVT in two cross-sectional studies [3Amitrano L. Guardascione M.A. Brancaccio V. Margaglione M. Manguso F. Iannaccone L. et al.Risk factors and clinical presentation of portal vein thrombosis in patients with liver cirrhosis.J Hepatol. 2004; 40: 736-741Abstract Full Text Full Text PDF PubMed Scopus (452) Google Scholar, 7Erkan O. Bozdayi A.M. Disibeyaz S. Oguz D. Ozcan M. Bahar K. et al.Thrombophilic gene mutations in cirrhotic patients with portal vein thrombosis.Eur J Gastroenterol Hepatol. 2005; 17: 339-343Crossref PubMed Scopus (66) Google Scholar]. More importantly, a prospective follow-up study of cirrhotic patients without PVT at inclusion showed PVT to develop significantly more frequently in those patients with the prothrombin gene mutation [[4]Amitrano L. Brancaccio V. Guardascione M.A. Margaglione M. Sacco M. Martino R. et al.Portal vein thrombosis after variceal endoscopic sclerotherapy in cirrhotic patients: role of genetic thrombophilia.Endoscopy. 2002; 34: 535-538Crossref PubMed Scopus (81) Google Scholar]. However, no association between prothrombin gene mutation and PVT was demonstrated in another study [[8]Mangia A. Villani M.R. Cappucci G. Santoro R. Ricciardi R. Facciorusso D. et al.Causes of portal venous thrombosis in cirrhotic patients: the role of genetic and acquired factors.Eur J Gastroenterol Hepatol. 2005; 17: 745-751Crossref PubMed Scopus (76) Google Scholar]. However, the latter was a cross-sectional study and patients with PVT had more severe liver disease than those without PVT [8Mangia A. Villani M.R. Cappucci G. Santoro R. Ricciardi R. Facciorusso D. et al.Causes of portal venous thrombosis in cirrhotic patients: the role of genetic and acquired factors.Eur J Gastroenterol Hepatol. 2005; 17: 745-751Crossref PubMed Scopus (76) Google Scholar, 15Walker A.P. Portal vein thrombosis: what is the role of genetics?.Eur J Gastroenterol Hepatol. 2005; 17: 705-707Crossref PubMed Scopus (22) Google Scholar]. The discrepancy in the findings further highlights the importance of patient selection when looking for prognostic risk factors [[13]Guyatt G. Determining prognosis and creating clinical decision rules.in: Haynes B. Sackett D.L. Guyatt G. Tulliez M. Clinical epidemiology. 3rd ed. Lippincott Williams & Wilkins, 2006: 323-355Google Scholar]. Factor V Leiden mutation can be found in 6.7% [16Bombeli T. Basic A. Fehr J. Prevalence of hereditary thrombophilia in patients with thrombosis in different venous systems.Am J Hematol. 2002; 70: 126-132Crossref PubMed Scopus (108) Google Scholar, 17Price D.T. Ridker P.M. Factor V Leiden mutation and the risks for thromboembolic disease: a clinical perspective.Ann Intern Med. 1997; 127: 895-903Crossref PubMed Scopus (288) Google Scholar], prothrombin mutation in 2.5% [[16]Bombeli T. Basic A. Fehr J. Prevalence of hereditary thrombophilia in patients with thrombosis in different venous systems.Am J Hematol. 2002; 70: 126-132Crossref PubMed Scopus (108) Google Scholar] and any inherited prothrombotic conditions in up to 9.1% of healthy people [[16]Bombeli T. Basic A. Fehr J. Prevalence of hereditary thrombophilia in patients with thrombosis in different venous systems.Am J Hematol. 2002; 70: 126-132Crossref PubMed Scopus (108) Google Scholar]. Assuming that hereditary coagulation defects do not decrease – and may even increase – the probability of having a chronic liver disease [18Wanless I.R. Wong F. Blendis L.M. Greig P. Heathcote E.J. Levy G. Hepatic and portal vein thrombosis in cirrhosis: possible role in development of parenchymal extinction and portal hypertension.Hepatology. 1995; 21: 1238-1247PubMed Google Scholar, 19Valla D.C. Thrombosis and anticoagulation in liver disease.Hepatology. 2008; 47: 1384-1393Crossref PubMed Scopus (85) Google Scholar, 20Webster G.J. Burroughs A.K. Riordan S.M. Review article: portal vein thrombosis – new insights into aetiology and management.Aliment Pharmacol Ther. 2005; 21: 1-9Crossref PubMed Scopus (109) Google Scholar], it is likely that a similar rate of these inherited alterations will be found in patients with cirrhosis and may play a role in the development of PVT. Further to these issues regarding patient selection, is US-Doppler the imaging technique of choice for excluding PVT at baseline? Efficiency of US depends not only on the expertise of the individual radiologist but also on the extent of PVT. It is likely that, even in experienced hands, US-Doppler studies aimed specifically at evaluating portal venous patency may miss some patients that already have PVT. Nevertheless, despite the risk of some false negatives, and due to a better cost or safety profile in comparison to angioCT or angioMR, US-Doppler will probably remain the imaging technique of choice, while angioCT or angioMR should be performed to confirm PVT and determine its extension once diagnosed with US-Doppler. It may be argued that, in patients with cirrhosis, prothrombotic disorders, if present, might be counterbalanced by the hypocoagulable state related to the impaired synthesis of procoagulant factors due to liver insufficiency. However, the complex interaction among procoagulant and anticoagulant mechanisms found in cirrhosis rarely results in a hypocoagulable state and bleeding, but may even lead to an hypercoagulable state [21Northup P.G. Hypercoagulation in liver disease.Clin Liver Dis. 2009; 13: 109-116Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar, 22Tripodi A. Mannucci P.M. Abnormalities of hemostasis in chronic liver disease: reappraisal of their clinical significance and need for clinical and laboratory research.J Hepatol. 2007; 46: 727-733Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar, 23Tripodi A. Salerno F. Chantarangkul V. Clerici M. Cazzaniga M. Primignani M. et al.Evidence of normal thrombin generation in cirrhosis despite abnormal conventional coagulation tests.Hepatology. 2005; 41: 553-558Crossref PubMed Scopus (557) Google Scholar] facilitating PVT. A point of great interest in the study by Zocco et al. shows that once liver insufficiency and the accompanying decrease in natural anticoagulant proteins are taken into account, portal blood flow velocity is a major independent risk factor for PVT. Thus, one of the components of Virchow's triad is confirmed to play a similar role in the splanchnic veins as in other deep veins. Furthermore, taken together, the findings of Zocco et al. and other investigators [3Amitrano L. Guardascione M.A. Brancaccio V. Margaglione M. Manguso F. Iannaccone L. et al.Risk factors and clinical presentation of portal vein thrombosis in patients with liver cirrhosis.J Hepatol. 2004; 40: 736-741Abstract Full Text Full Text PDF PubMed Scopus (452) Google Scholar, 4Amitrano L. Brancaccio V. Guardascione M.A. Margaglione M. Sacco M. Martino R. et al.Portal vein thrombosis after variceal endoscopic sclerotherapy in cirrhotic patients: role of genetic thrombophilia.Endoscopy. 2002; 34: 535-538Crossref PubMed Scopus (81) Google Scholar, 7Erkan O. Bozdayi A.M. Disibeyaz S. Oguz D. Ozcan M. Bahar K. et al.Thrombophilic gene mutations in cirrhotic patients with portal vein thrombosis.Eur J Gastroenterol Hepatol. 2005; 17: 339-343Crossref PubMed Scopus (66) Google Scholar, 24Valla D.C. Condat B. Portal vein thrombosis in adults: pathophysiology, pathogenesis and management.J Hepatol. 2000; 32: 865-871Abstract Full Text Full Text PDF PubMed Scopus (320) Google Scholar, 25Denninger M.H. Chait Y. Casadevall N. Hillaire S. Guillin M.C. Bezeaud A. et al.Cause of portal or hepatic venous thrombosis in adults: the role of multiple concurrent factors.Hepatology. 2000; 31: 587-591Crossref PubMed Scopus (601) Google Scholar] indicate that, in the presence or absence of cirrhosis, PVT should be considered a multifactorial disorder resulting from the combination of inherited and acquired risk factors, including a reduction in portal blood flow among the latter. Measurement of portal blood flow is a quick, easy and non-invasive procedure and is widely available. Therefore, a finding of a reduction in portal blood flow below the threshold of 15 cm/s may be, alone or in association to other factors, a useful parameter to consider when evaluating the risk of PVT in patients with cirrhosis. A further word of caution is warranted before extrapolating the data by Zocco et al. It should be kept in mind that over 50% of cirrhotic patients have esophageal varices at diagnosis [[26]Garcia-Pagan J.C. De Gotardi A. Bosch J. Review article: the modern management of portal hypertension – primary and secondary prophylaxis of variceal bleeding in cirrhotic patients.Aliment Pharmacol Ther. 2008; 28: 178-186Crossref PubMed Scopus (66) Google Scholar], so a high proportion of them will be placed on chronic treatment with non-selective beta-blockers. As these drugs reduce portal blood flow and velocity [[27]Bosch J. Mastai R. Kravetz D. Bruix J. Gaya J. Rigau J. et al.Effects of propranolol on azygos venous blood flow and hepatic and systemic hemodynamics in cirrhosis.Hepatology. 1984; 4: 1200-1205Crossref PubMed Scopus (285) Google Scholar], it will be interesting to assess whether reduced portal blood velocity under non-selective beta-blockers is equally useful in predicting the risk of developing PVT. Zocco et al. suggest that patients with a portal blood velocity below 15 cm/s, may benefit from prophylactic anticoagulation to prevent PVT. This suggestion is clinically relevant as, according to their data, 31.5% of unselected cirrhotic patients admitted to a teaching hospital fulfilled this criterion, and more than 45% of these are expected to develop PVT within a year. However, the risk and benefit of such an approach remains to be assessed. First, it is still unclear whether the occurrence of PVT on a low portal flow velocity is an independent marker for complications and death. Second, it remains to be ascertained whether anticoagulation in this context of low portal blood flow velocity will prevent PVT from developing. Lastly, it should be seen to what extent prevention of portal vein thrombosis in this context of low portal vein flow velocity is able to impact favorably on the course of the disease. Further studies aimed to identify factors that may help to select cirrhotic patients at high risk of developing PVT are warranted. These studies should include a large number of all comers cirrhotic patients in which PVT and hepatocellular carcinoma must be explicitly excluded, using a cost-effective, high sensitive imaging technique. Clinical and laboratory features, screening of hereditary and acquired prothrombotic disorders, and US and US-Doppler parameters at baseline must be carefully recorded and patients submitted to prospective follow-up with scheduled imaging studies evaluating portal vein patency. This will be a necessary step before designing studies aimed at preventing the development of PVT.