Unconjugated bilirubin inhibits proteolytic cleavage of von Willebrand factor by ADAMTS13 protease

Journal of Thrombosis and Haemostasis : JTH
R-N LuX L Zheng

Abstract

Bilirubin is a yellow breakdown product of heme catabolism. Increased serum levels of unconjugated bilirubin are conditions commonly seen in premature neonates and adults with acute hemolysis including thrombotic microangiopathy. Previous studies have shown that unconjugated bilirubin lowers plasma ADAMTS13 activity, but the mechanism is not fully understood. The study is to determine whether unconjugated bilirubin directly inhibits the cleavage of von Willebrand factor (VWF) and its analogs by ADAMTS13. Fluorogenic, surface-enhanced laser desorption/ionization time-of-flight mass spectrometric assay, and Western blotting analyses were used to address this question. Unconjugated bilirubin inhibits the cleavage of F485-rVWF73-H, D633-rVWF73-H, and GST-rVWF71-11K by ADAMTS13 in a concentration-dependent manner with a half-maximal inhibitory concentration of ~13, ~70, and ~17 μmol L(-1) , respectively. Unconjugated bilirubin also dose-dependently inhibits the cleavage of multimeric VWF by ADAMTS13 under denaturing conditions. The inhibitory activity of bilirubin on the cleavage of D633-rVWF73-H and multimeric VWF, but not F485-rVWF73-H, was eliminated after incubation with bilirubin oxidase that converts bilirubin to biliverdin. F...Continue Reading

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Citations

Feb 16, 2016·Trends in Molecular Medicine·Lubka T RoumeninaJordan D Dimitrov
Oct 23, 2015·American Journal of Hematology·Ciprian B AneaJulia E Brittain
Jul 17, 2020·International Journal of Laboratory Hematology·Ian MackieRoss Baker
Feb 5, 2021·Research and Practice in Thrombosis and Haemostasis·Nicolas BerangerAgnès Veyradier
Mar 7, 2021·Journal of Thrombosis and Thrombolysis·Xin ZhangHong Chen
May 15, 2021·Blood Reviews·Laura Delvasto-NuñezSacha Zeerleder

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