To the Editor:

Ferlitsch et al. report on the utility of von Willebrand factor (vWF) in predicting portal hypertension (PH), decompensation, and death in patients with cirrhosis.[1] We wish to comment on a potential mechanism to account for this association.

Physiologically, vWF facilitates platelet adhesion at sites of endothelial damage. vWF is normally secreted by the endothelium as ultralarge vWF (ULvWF) multimers and cleaved into smaller forms by ADAMTS13 (a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13).[2] The presence of ULvWF multimers may reflect reduced ADAMTS13 activity. Decreased ADAMTS13 activity is associated with microvascular occlusion in thrombotic microangiopathies.[2] If operative within the liver, these factors would potentially influence the natural history of liver disease, intensify PH,[3] and thus account for their prognostic significance.

We reported an association of gut disorders with idiopathic noncirrhotic intrahepatic PH (NCIPH), which results from portal venular obliteration.[4] Serum levels of inflammatory cytokines, which are known to stimulate ULvWF multimer release and inhibit ADAMTS13 synthesis,[5, 6] are elevated in patients with celiac disease.[7] Therefore, we studied vWF/ADAMTS13 balance in NCIPH. We found ADAMTS13 deficiency and ULvWF multimers in NCIPH patients in both portal[8] and portopulmonary[9] hypertension and deduced that the above-described mechanisms may be causatively implicated.

The assay used by Ferlitsch et al.[1] would have detected all molecular sizes of vWF, without differentiating between them. It would be interesting to analyze whether ULvWF multimers and ADAMTS13 also have prognostic significance in these patients.


  • 1Hepatology Department, Christian Medical College, Vellore, India

  • 2Department of Medicine, University Hospitals of Leicester, Leicester, UK

  • 3Hemostasis Research Unit, Department of Hematology, University College London, London, UK

  • 4Liver Unit, University Hospitals of, Birmingham, Birmingham, UK


  1. Top of page
  2. References
  • 1
    Ferlitsch M, Reiberger T, Hoke M, Salzl P, Schwengerer B, Ulbrich G, et al. von Willebrand factor as new noninvasive predictor of portal hypertension, decompensation, and mortality in patients with liver cirrhosis. Hepatology 2012;56:1439-1447.
  • 2
    Moake JL. Thrombotic microangiopathies. N Engl J Med 2002;347:589-600.
  • 3
    Wanless IR, Wong F, Blendis LM, Greig P, Heathcote EJ, Levy G. Hepatic and portal vein thrombosis in cirrhosis: possible role in development of parenchymal extinction and portal hypertension. Hepatology 1995;21:1238-1247.
  • 4
    Eapen CE, Nightingale P, Hubscher SG, Lane PJ, Plant T, Velissaris D, et al. Non-cirrhotic intrahepatic portal hypertension: associated gut diseases and prognostic factors. Dig Dis Sci 2011;56:227-235.
  • 5
    Bernardo A, Ball C, Nolasco L, Moake JF, Dong JF. Effects of inflammatory cytokines on the release and cleavage of the endothelial cell- derived ultra large vWF multimers under flow. Blood 2004;104:100-106.
  • 6
    Cao WJ, Niiya M, Zheng XW, Shang DZ, Zheng XL. Inflammatory cytokines inhibit ADAMTS13 synthesis in hepatic stellate cells and endothelial cells. J Thromb Haemost 2008;6:1233-1235.
  • 7
    Manavalan JS, Hernandez L, Shah JG, Konikkara J, Naiyer AJ, Lee AR, et al. Serum cytokine elevations in celiac disease: association with disease presentation. Hum Immunol 2010;71:50-57.
  • 8
    Mackie I, Eapen CE, Neil D, Lawrie AS, Chitolie A, Shaw JC, et al. Idiopathic non-cirrhotic intrahepatic portal hypertension (NCIPH) is associated with sustained ADAMTS13 deficiency. Dig Dis Sci 2011;56:2456-2465.
  • 9
    Elias JE, Mackie I, Eapen CE, Chu P, Shaw JC, Elias E. Porto-pulmonary hypertension exacerbated by platelet transfusion in a patient with ADAMTS13 deficiency. J Hepatol 2012 Nov 10. doi:10.1016/j.jhep.2012.11.003.