Skip to main content
SpringerLink
Log in

Presence of portal vein thrombosis in liver cirrhosis is strongly associated with low levels of ADAMTS-13: a pilot study

  • IM - ORIGINAL
  • Published:
Internal and Emergency Medicine Aims and scope Submit manuscript

Abstract

Portal vein thrombosis (PVT) dramatically changes the prognosis of cirrhotic patients, especially those waiting for liver transplantation. However, the possible contribution to PVT of von Willebrand factor (VWF) and ADAMTS-13 is poorly documented. The aim of our study was to assess the presence of alterations of VWF and ADAMTS-13 serum levels in cirrhotic patients with PVT. Twenty-four patients with PVT (group PVT) and 60 without PVT (group without PVT) were enrolled. A comprehensive analysis of biochemical and hemostatic parameters was performed. ADAMTS-13 activity was significantly lower in group A (median 16.8 vs. 69.1 %, p = 0.0047). Group PVT, compared to group without PVT, showed a significantly higher VWF:act, (median 308.4 vs 203.3 %, p = 0.032), whereas no difference was observed for VWF:Ag, FVIII level and the presence of risk factors for venous thromboembolism. No correlation was found between the Child–Pugh score and ADAMTS-13 activity. In multivariable logistic regression analysis performed on data concerning both group PVT and without PVT, only the ADAMTS-13 activity (p = 0.007) was independently and inversely associated with PVT. In conclusion, ADAMTS-13 activity is independently associated with PVT in cirrhotic patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

PVT:

Portal vein thrombosis

VWF:

von Willebrand factor

ADAMTS-13:

A disintegrin and metalloprotease with thrombospondin 1 repeats Nr. 13

VTE:

Venous thromboembolism

VWF:act:

VWF activity

VWF:Ag:

VWF antigen

UL-VWF:

Ultralarge VWF

PT:

Prothrombin time

APTT:

Activated partial thromboplastin time

References

  1. Moake JL, Turner NA, Stathopoulos NA, Nolasco LH, Hellums JD (1986) Involvement of large plasma von Willebrand factor (vWF) multimers and unusually large vWF forms derived from endothelial cells in shear stress-induced platelet aggregation. J Clin Invest 78(6):1456–1461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. George JN, Nester CM (2014) Syndromes of thrombotic microangiopathy. N Engl J Med 371(7):654–666

    Article  CAS  PubMed  Google Scholar 

  3. George JN, Li X, McMinn JR, Terrell DR, Vesely SK, Selby GB (2004) Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome following allogeneic HPC transplantation: a diagnostic dilemma. Transfusion 44(2):294–304

    Article  PubMed  Google Scholar 

  4. Di Stasio E, Lancellotti S, Peyvandi F, Palla R, Mannucci PM, De Cristofaro R (2008) Mechanistic studies on ADAMTS13 catalysis. Biophys J 95(5):2450–2461

    Article  PubMed  PubMed Central  Google Scholar 

  5. Soejima K, Mimura N, Hirashima M, Maeda H, Hamamoto T, Nakagaki T, Nozaki C (2001) A novel human metalloprotease synthesized in the liver and secreted into the blood: possibly, the von Willebrand factor-cleaving protease? J Biochem 130(4):475–480

    Article  CAS  PubMed  Google Scholar 

  6. Uemura M, Tatsumi K, Matsumoto M, Fujimoto M, Matsuyama T, Ishikawa M, Iwamoto TA, Mori T, Wanaka A, Fukui H, Fujimura Y (2005) Localization of ADAMTS13 to the stellate cells of human liver. Blood 106(3):922–924

    Article  CAS  PubMed  Google Scholar 

  7. Turner NA, Nolasco L, Ruggeri ZM, Moake JL (2009) Endothelial cell ADAMTS-13 and VWF: production, release, and VWF string cleavage. Blood 114(24):5102–5111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Suzuki M, Murata M, Matsubara Y, Uchida T, Ishihara H, Shibano T, Ashida S, Soejima K, Okada Y, Ikeda Y (2004) Detection of von Willebrand factor-cleaving protease (ADAMTS-13) in human platelets. Biochem Biophys Res Commun 313(1):212–216

    Article  CAS  PubMed  Google Scholar 

  9. Manea M, Kristoffersson A, Schneppenheim R, Saleem MA, Mathieson PW, Morgelin M, Bjork P, Holmberg L, Karpman D (2007) Podocytes express ADAMTS13 in normal renal cortex and in patients with thrombotic thrombocytopenic purpura. Br J Haematol 138(5):651–662

    Article  CAS  PubMed  Google Scholar 

  10. Lancellotti S, De Cristofaro R (2011) Structure and proteolytic properties of ADAMTS13, a metalloprotease involved in the pathogenesis of thrombotic microangiopathies. Prog Mol Biol Transl Sci 99:105–144

    Article  CAS  PubMed  Google Scholar 

  11. Ono T, Mimuro J, Madoiwa S, Soejima K, Kashiwakura Y, Ishiwata A, Takano K, Ohmori T, Sakata Y (2006) Severe secondary deficiency of von Willebrand factor-cleaving protease (ADAMTS13) in patients with sepsis-induced disseminated intravascular coagulation: its correlation with development of renal failure. Blood 107(2):528–534

    Article  CAS  PubMed  Google Scholar 

  12. Lattuada A, Rossi E, Calzarossa C, Candolfi R, Mannucci PM (2003) Mild to moderate reduction of a von Willebrand factor cleaving protease (ADAMTS-13) in pregnant women with HELLP microangiopathic syndrome. Haematologica 88(9):1029–1034

    CAS  PubMed  Google Scholar 

  13. Reiter RA, Varadi K, Turecek PL, Jilma B, Knobl P (2005) Changes in ADAMTS13 (von-Willebrand-factor-cleaving protease) activity after induced release of von Willebrand factor during acute systemic inflammation. Thromb Haemost 93(3):554–558

    CAS  PubMed  Google Scholar 

  14. Claus RA, Bockmeyer CL, Sossdorf M, Losche W (2010) The balance between von-Willebrand factor and its cleaving protease ADAMTS13: biomarker in systemic inflammation and development of organ failure? Curr Mol Med 10(2):236–248

    Article  CAS  PubMed  Google Scholar 

  15. Mannucci PM, Canciani MT, Forza I, Lussana F, Lattuada A, Rossi E (2001) Changes in health and disease of the metalloprotease that cleaves von Willebrand factor. Blood 98(9):2730–2735

    Article  CAS  PubMed  Google Scholar 

  16. Niiya M, Uemura M, Zheng XW, Pollak ES, Dockal M, Scheiflinger F, Wells RG, Zheng XL (2006) Increased ADAMTS-13 proteolytic activity in rat hepatic stellate cells upon activation in vitro and in vivo. J Thromb Haemost 4(5):1063–1070

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Uemura M, Fujimura Y, Matsumoto M, Ishizashi H, Kato S, Matsuyama T, Isonishi A, Ishikawa M, Yagita M, Morioka C, Yoshiji H, Tsujimoto T, Kurumatani N, Fukui H (2008) Comprehensive analysis of ADAMTS13 in patients with liver cirrhosis. Thromb Haemost 99(6):1019–1029

    CAS  PubMed  Google Scholar 

  18. Lisman T, Bongers TN, Adelmeijer J, Janssen HL, de Maat MP, de Groot PG, Leebeek FW (2006) Elevated levels of von Willebrand Factor in cirrhosis support platelet adhesion despite reduced functional capacity. Hepatology 44(1):53–61

    Article  CAS  PubMed  Google Scholar 

  19. Takaya H, Uemura M, Fujimura Y, Matsumoto M, Matsuyama T, Kato S, Morioka C, Ishizashi H, Hori Y, Fujimoto M, Tsujimoto T, Kawaratani H, Toyohara M, Kurumatani N, Fukui H (2012) 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 42(5):459–472

    Article  PubMed  Google Scholar 

  20. Cao WJ, Niiya M, Zheng XW, Shang DZ, Zheng XL (2008) Inflammatory cytokines inhibit ADAMTS13 synthesis in hepatic stellate cells and endothelial cells. J Thromb Haemost 6(7):1233–1235

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Bernardo A, Ball C, Nolasco L, Moake JF, Dong JF (2004) Effects of inflammatory cytokines on the release and cleavage of the endothelial cell-derived ultralarge von Willebrand factor multimers under flow. Blood 104(1):100–106

    Article  CAS  PubMed  Google Scholar 

  22. Ferro D, Quintarelli C, Lattuada A, Leo R, Alessandroni M, Mannucci PM, Violi F (1996) High plasma levels of von Willebrand factor as a marker of endothelial perturbation in cirrhosis: relationship to endotoxemia. Hepatology 23(6):1377–1383

    Article  CAS  PubMed  Google Scholar 

  23. Ferlitsch M, Reiberger T, Hoke M, Salzl P, Schwengerer B, Ulbrich G, Payer BA, Trauner M, Peck-Radosavljevic M, Ferlitsch A (2012) von Willebrand factor as new noninvasive predictor of portal hypertension, decompensation and mortality in patients with liver cirrhosis. Hepatology 56(4):1439–1447

    Article  CAS  PubMed  Google Scholar 

  24. Francoz C, Belghiti J, Vilgrain V, Sommacale D, Paradis V, Condat B, Denninger MH, Sauvanet A, Valla D, Durand F (2005) Splanchnic vein thrombosis in candidates for liver transplantation: usefulness of screening and anticoagulation. Gut 54(5):691–697

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Janssen HL, Meinardi JR, Vleggaar FP, van Uum SH, Haagsma EB, van Der Meer FJ, van Hattum J, Chamuleau RA, Adang RP, Vandenbroucke JP, van Hoek B, Rosendaal FR (2000) Factor V Leiden mutation, prothrombin gene mutation, and deficiencies in coagulation inhibitors associated with Budd–Chiari syndrome and portal vein thrombosis: results of a case-control study. Blood 96(7):2364–2368

    CAS  PubMed  Google Scholar 

  26. Primignani M, Martinelli I, Bucciarelli P, Battaglioli T, Reati R, Fabris F, Dell’era A, Pappalardo E, Mannucci PM (2005) Risk factors for thrombophilia in extrahepatic portal vein obstruction. Hepatology 41(3):603–608

    Article  CAS  PubMed  Google Scholar 

  27. Parikh S, Shah R, Kapoor P (2010) Portal vein thrombosis. Am J Med 123(2):111–119

    Article  PubMed  Google Scholar 

  28. D’Amico M, Pasta F, Pasta L (2015) 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

  29. Amitrano L, Guardascione MA, Ames PR, Margaglione M, Iannaccone L, Brancaccio V, Balzano A (2006) Increased plasma prothrombin concentration in cirrhotic patients with portal vein thrombosis and prothrombin G20210A mutation. Thromb Haemost 95(2):221–223

    CAS  PubMed  Google Scholar 

  30. Zoller B, Li X, Sundquist J, Sundquist K (2010) Familial risks of unusual forms of venous thrombosis: a nationwide epidemiological study in Sweden. J Intern Med 270(2):158–165

    Article  PubMed  Google Scholar 

  31. Zocco MA, Di Stasio E, De Cristofaro R, Novi M, Ainora ME, Ponziani F, Riccardi L, Lancellotti S, Santoliquido A, Flore R, Pompili M, Rapaccini GL, Tondi P, Gasbarrini GB, Landolfi R, Gasbarrini A (2009) Thrombotic risk factors in patients with liver cirrhosis: correlation with MELD scoring system and portal vein thrombosis development. J Hepatol 51(4):682–689

    Article  PubMed  Google Scholar 

  32. Ponziani FR, Zocco MA, Campanale C, Rinninella E, Tortora A, Di Maurizio L, Bombardieri G, De Cristofaro R, De Gaetano AM, Landolfi R, Gasbarrini A (2010) Portal vein thrombosis: insight into physiopathology, diagnosis, and treatment. World J Gastroenterol 16(2):143–155

    Article  PubMed  PubMed Central  Google Scholar 

  33. Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R (1973) Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 60(8):646–649

    Article  CAS  PubMed  Google Scholar 

  34. Yerdel MA, Gunson B, Mirza D, Karayalcin K, Olliff S, Buckels J, Mayer D, McMaster P, Pirenne J (2000) Portal vein thrombosis in adults undergoing liver transplantation: risk factors, screening, management, and outcome. Transplantation 69(9):1873–1881

    Article  CAS  PubMed  Google Scholar 

  35. de Maistre E, Volot F, Mourey G, Aho LS, Ternisien C, Briquel ME, Bertrand MA, Tardy B, Frotscher B, Nguyen P, Dumont L, Vandroux D, Hezard N, Trossaert M (2014) Performance of two new automated assays for measuring von Willebrand activity: HemosIL AcuStar and Innovance. Thromb Haemost 112(4):825–830

    Article  PubMed  Google Scholar 

  36. Stufano F, Lawrie AS, La Marca S, Berbenni C, Baronciani L, Peyvandi F (2014) A two-centre comparative evaluation of new automated assays for von Willebrand factor ristocetin cofactor activity and antigen. Haemophilia 20(1):147–153

    Article  CAS  PubMed  Google Scholar 

  37. Lancellotti S, Dragani A, Ranalli P, Petrucci G, Basso M, Tartaglione R, Rocca B, De Cristofaro R (2016) Qualitative and quantitative modifications of von Willebrand factor in patients with essential thrombocythemia and controlled platelet count. J Thromb Haemost 13(7):1226–1237

    Article  Google Scholar 

  38. Kokame K, Nobe Y, Kokubo Y, Okayama A, Miyata T (2005) FRETS-VWF73, a first fluorogenic substrate for ADAMTS13 assay. Br J Haematol 129(1):93–100

    Article  CAS  PubMed  Google Scholar 

  39. Lancellotti S, De Filippis V, Pozzi N, Peyvandi F, Palla R, Rocca B, Rutella S, Pitocco D, Mannucci PM, De Cristofaro R (2010) Formation of methionine sulfoxide by peroxynitrite at position 1606 of von Willebrand factor inhibits its cleavage by ADAMTS-13: a new prothrombotic mechanism in diseases associated with oxidative stress. Free Radic Biol Med 48(3):446–456

    Article  CAS  PubMed  Google Scholar 

  40. Meyer SC, Sulzer I, Lammle B, Kremer Hovinga JA (2007) Hyperbilirubinemia interferes with ADAMTS-13 activity measurement by FRETS-VWF73 assay: diagnostic relevance in patients suffering from acute thrombotic microangiopathies. J Thromb Haemost 5(4):866–867

    Article  CAS  PubMed  Google Scholar 

  41. Lancellotti S, Dragani A, Ranalli P, Petrucci G, Basso M, Tartaglione R, Rocca B, De Cristofaro R (2015) Qualitative and quantitative modifications of von Willebrand factor in patients with essential thrombocythemia and controlled platelet count. J Thromb Haemost

  42. Toh CH, Hoots WK (2007) The scoring system of the scientific and standardisation committee on disseminated intravascular coagulation of the international society on thrombosis and haemostasis: a 5-year overview. J Thromb Haemost 5(3):604–606

    Article  CAS  PubMed  Google Scholar 

  43. Jamieson NV (2000) Changing perspectives in portal vein thrombosis and liver transplantation. Transplantation 69(9):1772–1774

    Article  CAS  PubMed  Google Scholar 

  44. Amitrano L, Guardascione MA, Ames PR (2007) Coagulation abnormalities in cirrhotic patients with portal vein thrombosis. Clin Lab 53(9–12):583–589

    PubMed  Google Scholar 

  45. Hugenholtz GC, Adelmeijer J, Meijers JC, Porte RJ, Stravitz RT, Lisman T (2013) An unbalance between von Willebrand factor and ADAMTS13 in acute liver failure: implications for hemostasis and clinical outcome. Hepatology 58(2):752–761

    Article  CAS  PubMed  Google Scholar 

  46. Wiese S, Timm A, Nielsen LB, Goetze JP, Bendtsen F, Moller S (2016) Plasma ADAMTS-13 protein is not associated with portal hypertension or hemodynamic changes in patients with cirrhosis. Dig Liver Dis 48(4):404–408

    Article  CAS  PubMed  Google Scholar 

  47. Taniguchi S, Hashiguchi T, Ono T, Takenouchi K, Nakayama K, Kawano T, Kato K, Matsushita R, Nagatomo M, Nakamura S, Nakashima T, Maruyama I (2010) Association between reduced ADAMTS13 and diabetic nephropathy. Thromb Res 125(6):e310–e316

    Article  CAS  PubMed  Google Scholar 

  48. Tati R, Kristoffersson AC, Stahl AL, Morgelin M, Motto D, Satchell S, Mathieson P, Manea-Hedstrom M, Karpman D (2011) Phenotypic expression of ADAMTS13 in glomerular endothelial cells. PLoS One 6(6):e21587

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. DeLeve LD (2015) Liver sinusoidal endothelial cells in hepatic fibrosis. Hepatology 61(5):1740–1746

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Calvaruso V, Maimone S, Gatt A, Tuddenham E, Thursz M, Pinzani M, Burroughs AK (2008) Coagulation and fibrosis in chronic liver disease. Gut 57(12):1722–1727

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

RDC gratefully acknowledges financial support from the Ministry of University and Research of Italy (MIUR-Linea D1 2013–2014). No writing support was provided.

Author information

Authors and Affiliations

  1. Department of Oncology and Haematology, Institute of Internal Medicine and Geriatrics, Center for Hemorrhagic and Thrombotic Diseases and Haemophilia Center, “A. Gemelli” Hospital, Catholic University School of Medicine, Largo A. Gemelli, 00168, Rome, Italy

    Stefano Lancellotti, Maria Basso, Vito Veca, Monica Sacco & Raimondo De Cristofaro

  2. Department of Digestive, Endocrine and Metabolic System, Institute of Internal Medicine and Geriatrics, “A. Gemelli” Hospital, Catholic University School of Medicine, Rome, Italy

    Laura Riccardi & Maurizio Pompili

Authors
  1. Stefano Lancellotti
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maria Basso
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Vito Veca
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Monica Sacco
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Laura Riccardi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Maurizio Pompili
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Raimondo De Cristofaro
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Raimondo De Cristofaro.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Statement of human and animal rights

The procedures and the experiments performed in this investigation respected the ethical standards in the Helsinki Declaration of 1975, as revised in 2000 and 2008, as well as the Ethical Committee regulations of the Catholic University of the Sacred Heart.

Informed consent

Patients admitted at the “Fondazione Policlinico Universitario Agostino Gemelli” received systematic information about the use of de-identified anonymous data for the purpose of retrospective studies.

Additional information

Maurizio Pompili is the senior coauthor.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 30 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lancellotti, S., Basso, M., Veca, V. et al. Presence of portal vein thrombosis in liver cirrhosis is strongly associated with low levels of ADAMTS-13: a pilot study. Intern Emerg Med 11, 959–967 (2016). https://doi.org/10.1007/s11739-016-1467-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11739-016-1467-x

Keywords

Search

Navigation