Abstract
Background and aims
In cirrhosis, decreased portal flow velocity, thrombophilia factors, and portal hypertension
are considered risk factors for portal vein thrombosis (PVT). In cirrhosis, the transformation
of the stellate cells causes a progressive decrease of ADAMTS-13, while VWF multimers
secretion by endothelial cells is strongly enhanced. This imbalance leads to an accumulation
of ultra-large VWF multimers that in sinusoidal circulation could favor PVT both in
intra- and extra-hepatic branches, mostly in decompensated cirrhosis. This prospective
study was aimed at identifying possible clinical, biochemical, and hemostatic factors
predictive for non-tumoral PVT in a cohort of patients with compensated cirrhosis.
Methods
Seventynine compensated cirrhosis patients were prospectively followed for 48 months,
receiving a periodic Doppler-ultrasound liver examination associated with an extensive
evaluation of clinical, biochemical, and hemostatic profile.
Results
Five patients developed PVT (cumulative prevalence = 6.3%), occurring 4–36 months
after enrollment. In logistic regression analysis, the ADAMTS-13/VWF:GpIbR ratio < 0.4
was the only independent variable significantly associated with PVT (OR 14.6, 95%
C.I.:1.36–157.2, p = 0.027). A Cox-regression-analysis confirmed this finding (HR = 7.7, p = 0.027).
Conclusions
The ADAMTS-13/VWF ratio < 0.4 measured in compensated cirrhosis could be a reliable
predictive biomarker for PVT development, paving the way to novel therapeutic strategies
to prevent and treat PVT in this clinical setting.
Keywords
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References
- Current knowledge and management of portal vein thrombosis in cirrhosis.J Hepatol. 2021; 75: 442-453
- Changing concepts of cirrhotic coagulopathy.Am J Gastroenterol. 2017; 112: 274-281
- Thrombotic risk factors in patients with liver cirrhosis: correlation with MELD scoring system and portal vein thrombosis development.J Hepatol. 2009; 51: 682-689
- Causes and consequences of portal vein thrombosis in 1243 patients with cirrhosis: results of a longitudinal study.Hepatology. 2015; 61: 660-667
- Enoxaparin prevents portal vein thrombosis and liver decompensation in patients with advanced cirrhosis.Gastroenterology. 2012; 143 (1253–60 e4)
- Structure and proteolytic properties of ADAMTS13, a metalloprotease involved in the pathogenesis of thrombotic microangiopathies.Prog Mol Biol Transl Sci. 2011; 99: 105-144
- Localization of ADAMTS13 to the stellate cells of human liver.Blood. 2005; 106: 922-924
- Endothelial cell ADAMTS-13 and VWF: production, release, and VWF string cleavage.Blood. 2009; 114: 5102-5111
- Detection of von Willebrand factor-cleaving protease (ADAMTS-13) in human platelets.Biochem Biophys Res Commun. 2004; 313: 212-216
- Podocytes express ADAMTS13 in normal renal cortex and in patients with thrombotic thrombocytopenic purpura.Br J Haematol. 2007; 138: 651-662
- Syndromes of thrombotic microangiopathy.N Engl J Med. 2014; 371: 1847-1848
- The balance between von-Willebrand factor and its cleaving protease ADAMTS13: biomarker in systemic inflammation and development of organ failure?.Curr Mol Med. 2010; 10: 236-248
- von Willebrand factor/ADAMTS13 ratio at presentation of acute ischemic brain injury is predictive of outcome.Blood Adv. 2020; 4: 398-407
- VWF/ADAMTS13 imbalance, but not global coagulation or fibrinolysis, is associated with outcome and bleeding in acute liver failure.Hepatology. 2021; 73: 1882-1891
- ADAMTS13 activity may predict the cumulative survival of patients with liver cirrhosis in comparison with the child-turcotte-pugh score and the model for end-stage liver disease score.Hepatol Res. 2012; 42: 459-472
- Inflammatory cytokines inhibit ADAMTS13 synthesis in hepatic stellate cells and endothelial cells.J Thromb Haemost. 2008; 6: 1233-1235
- von Willebrand factor as new noninvasive predictor of portal hypertension, decompensation and mortality in patients with liver cirrhosis.Hepatology. 2012; 56: 1439-1447
- Procoagulant imbalance in patients with non-alcoholic fatty liver disease.J Hepatol. 2017; 66: 248-250
- Risk factors and clinical presentation of portal vein thrombosis in patients with liver cirrhosis.J Hepatol. 2004; 40: 736-741
- Qualitative and quantitative modifications of von Willebrand factor in patients with essential thrombocythemia and controlled platelet count.J Thromb Haemost. 2015; 13: 1226-1237
- Hereditary protein C-deficiency: laboratory values in transmitters and guidelines for the diagnostic procedure. Report on a study of the SSC subcommittee on protein C and protein S. protein C transmitter study group.Thromb Haemost. 1992; 68: 470-474
- Increased von Willebrand factor levels in polycythemia vera and phenotypic differences with essential thrombocythemia.Res Pract Thromb Haemost. 2020; 4: 413-421
- Platelet-VWF complexes are preferred substrates of ADAMTS13 under fluid shear stress.Blood. 2008; 111: 651-657
- Update on von Willebrand factor multimers: focus on high-molecular-weight multimers and their role in hemostasis.Blood Coagul Fibrinolysis. 2014; 25: 206-216
- No association of homocysteine, anticardiolipin antibody, and anti-beta2 glycoprotein I antibody with portal venous system thrombosis in liver cirrhosis.Clin Appl Thromb Hemost. 2021; 27 (10760296211010969)
- Platelet count/spleen diameter ratio for the noninvasive diagnosis of esophageal varices: results of a multicenter, prospective, validation study.Am J Gastroenterol. 2006; 101: 2511-2519
- Predicting portal thrombosis in cirrhosis: a prospective study of clinical, ultrasonographic and hemostatic factors.J Hepatol. 2021; 75: 1367-1376
- Hypercoagulability in cirrhosis: causes and consequences.J Thromb Haemost. 2011; 9: 1713-1723
- New insights into the pathogenesis, risk factors, and treatment of portal vein thrombosis in patients with cirrhosis.Semin Thromb Hemost. 2020; 46: 673-681
- Evidence that low protein C contributes to the procoagulant imbalance in cirrhosis.J Hepatol. 2013; 59: 265-270
- A shift in balance between profibrinolytic and antifibrinolytic factors causes enhanced fibrinolysis in cirrhosis.Gastroenterology. 1991; 101: 1382-1390
- Factor VIII expression in liver disease.Thromb Haemost. 2004; 91: 267-275
- ADAMTS13 activity to antigen ratio in physiological and pathological conditions associated with an increased risk of thrombosis.Br J Haematol. 2007; 138: 534-540
- Presence of portal vein thrombosis in liver cirrhosis is strongly associated with low levels of ADAMTS-13: a pilot study.Intern Emerg Med. 2016; 11: 959-967
- Elevated levels of von Willebrand factor in cirrhosis support platelet adhesion despite reduced functional capacity.Hepatology. 2006; 44: 53-61
- Nonmalignant portal vein thrombi in patients with cirrhosis consist of intimal fibrosis with or without a fibrin-rich thrombus.Hepatology. 2021;
- ADAMTS13 promotes angiogenesis and modulates VEGF-induced angiogenesis.Microvasc Res. 2012; 84: 109-115
- Overexpression of von Willebrand factor is an independent risk factor for pathogenesis of intimal hyperplasia: preliminary studies.J Vasc Surg. 2003; 37: 433-439
- The VWF/LRP4/alphaVbeta3-axis represents a novel pathway regulating proliferation of human vascular smooth muscle cells.Cardiovasc Res. 2021;
- Association of the von Willebrand factor-ADAMTS13 ratio with incident cardiovascular events in patients with peripheral arterial disease.Clin Appl Thromb Hemost. 2017; 23: 807-813
- Marked von Willebrand factor and factor VIII elevations in severe acute respiratory syndrome coronavirus-2-positive, but not severe acute respiratory syndrome coronavirus-2-negative, pneumonia: a case-control study.Blood Coagul Fibrinolysis. 2021; 32: 285-289
- Serial changes in von Willebrand factor-cleaving protease (ADAMTS13) and prognosis after acute myocardial infarction.Am J Cardiol. 2007; 100: 758-763
- Comprehensive analysis of ADAMTS13 in patients with liver cirrhosis.Thromb Haemost. 2008; 99: 1019-1029
- Increased von Willebrand Factor to ADAMTS13 ratio as a predictor of thrombotic complications following a major hepatectomy.Arch Surg. 2012; 147: 909-917
- Mechanistic studies on ADAMTS13 catalysis.Biophys J. 2008; 95: 2450-2461
- Increased platelet aggregation in patients with decompensated cirrhosis indicates higher risk of further decompensation and death.J Hepatol. 2022;
- Tissue distribution of factor VIII gene expression in vivo–a closer look.Thromb Haemost. 2001; 86: 855-861
- Studies on capillarization of the hepatic sinusoids in alcoholic liver disease.Alcohol Alcohol Suppl. 1993; 1B: 77-84
- Anticoagulation for the treatment of portal vein thrombosis in liver cirrhosis: a systematic review and meta-analysis of observational studies.Eur J Intern Med. 2015; 26: 23-29
- Effects of inflammatory cytokines on the release and cleavage of the endothelial cell-derived ultralarge von Willebrand factor multimers under flow.Blood. 2004; 104: 100-106
- Targeting von Willebrand factor in liver diseases: a novel therapeutic strategy?.J Thromb Haemost. 2021; 19: 1390-1408
- Caplacizumab treatment for acquired thrombotic thrombocytopenic purpura.N Engl J Med. 2019; 380: 335-346
- Recombinant ADAMTS13 reduces tissue plasminogen activator-induced hemorrhage after stroke in mice.Ann Neurol. 2013; 73: 189-198
Article info
Publication history
Published online: June 29, 2022
Accepted:
June 7,
2022
Received:
March 12,
2022
Identification
Copyright
© 2022 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
