Abstract
Thrombomodulin (TM) functions in coagulation, fibrinolysis and inflammation by its
cofactor activity for protein C, thrombin-activatable fibrinolysis inhibitor (TAFI)
activation and high mobility group box 1 (HMGB1) degradation induced by thrombin.
It has been widely reported that mutations in TM are related to thromboembolic diseases
but hardly in lectin domain. Here we report our findings about the functional deficiencies
in TM caused by substitution of aspartate with tyrosine at residue 126. Three patients
suffering from recurrent thromboembolic diseases were identified with this mutation
and their plasma soluble TM levels were decreased. Transfected cells expressing wild-type
TM or the variant and corresponding proteins were used to examine TM functions in
vitro. The cofactor activity of the mutant for protein C, TAFI activation was reduced
to approximately 50% and 60% respectively. Loss in anti-inflammation due to weakened
HMGB1 degradation was also observed. And the study with thrombosis models of mice
suggested the decreased inhibition of thrombus development of the mutant. Together
the results showed deleterious changes on TM function caused by this mutation, which
may explain the thrombophilia tendency of the patients. This work provided supportive
evidence that mutation in lectin domain of TM might be related to thrombotic diseases
and may help us better understand the physiological roles of TM.
Abbreviations:
TM (thrombomodulin), EGF (epidermal growth factor), Ser/Thr (serine/threonine), sTM (soluble thrombomodulin), PC (protein C), APC (activated protein C), TAFI (thrombin-activatable fibrinolysis inhibitor), TAFIa (activated TAFI), tPA (tissue-type plasminogen activator), HMGB1 (high mobility group box 1), Hip-Arg (hippuryl-L-arginine), Asp/D (aspartate), Tyr/Y (tyrosine), PC/PS/PE (L-a-phosphatidylcholine/L-a-phosphatidylserine/L-a-phosphatidylethanolamine), PPACK (H-D-Phe-Pro-Arg-chloromethylketone), RT-PCR (real-time reverse-transcription polymerase chain reaction), SDS-PAGE (sodium dodecyl sulfate polyacrylamide gel electrophoresis), SPR (Surface Plasmon Resonance), PBS (phosphate-buffered saline), TF (tissue factor), IVC (inferior vena cava), KD (affinity constant), MFI (median fluorescence intensity)To read this article in full you will need to make a payment
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Article Info
Publication History
Published online: July 31, 2022
Accepted:
July 22,
2022
Received in revised form:
July 13,
2022
Received:
May 17,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2022 Elsevier Inc. All rights reserved.
