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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References
- Thrombomodulin.J Thromb Haemost. 2003; 1: 1515-1524
- Thrombomodulin structure and function.Thromb Haemost. 1997; 78: 392-395
- Identification of an endothelial cell cofactor for thrombin-catalyzed activation of protein C.Proc Natl Acad Sci U S A. 1981; 78: 2249-2252
- Structural basis for the anticoagulant activity of the thrombin-thrombomodulin complex.Nature. 2000; 404: 518-525
- Structure and function of thrombomodulin: a natural anticoagulant.Blood. 1990; 75: 329-336
- Thrombomodulin is present in human plasma and urine.J Clin Invest. 1985; 76: 2178-2181
- Inactivation of human coagulation factor V by activated protein C.J Biol Chem. 1983; 258: 1914-1920
- Regulation of the protein C anticoagulant and antiinflammatory pathways.Curr Med Chem. 2010; 17: 2059-2069
- Functional domains of membrane-bound human thrombomodulin. EGF-like domains four to six and the serine/threonine-rich domain are required for cofactor activity.J Biol Chem. 1992; 267: 6164-6170
- Activation of thrombin-activable fibrinolysis inhibitor requires epidermal growth factor-like domain 3 of thrombomodulin and is inhibited competitively by protein C.J Biol Chem. 1998; 273: 12135-12139
- Exploring traditional and nontraditional roles for thrombomodulin.Blood. 2018; 132: 148-158
- TAFI, or plasma procarboxypeptidase B, couples the coagulation and fibrinolytic cascades through the thrombin-thrombomodulin complex.J Biol Chem. 1996; 271: 16603-16608
- Proteolytic cleavage of high mobility group box 1 protein by thrombin-thrombomodulin complexes.Arterioscler Thromb Vasc Biol. 2008; 28: 1825-1830
- Thrombomodulin and its role in inflammation.Semin Immunopathol. 2012; 34: 107-125
- The role of thrombomodulin lectin-like domain in inflammation.J Biomed Sci. 2012; 19: 34
- Naturally occurring mutations in the thrombomodulin gene leading to impaired expression and function.Blood. 2002; 99: 3646-3653
- Common genetic risk factors for venous thrombosis in the Chinese population.Am J Hum Genet. 2013; 92: 177-187
- Effect of different types of thrombin inhibitors on thrombin/thrombomodulin modulated activation of protein C in vitro.Thromb Res. 2001; 104: 475-486
- Plasma TAFI levels influence the clot lysis time in healthy individuals in the presence of an intact intrinsic pathway of coagulation.Thromb Haemost. 1998; 80: 829-835
- Ferric chloride-induced arterial thrombosis in mice.Curr Protoc Mouse Biol. 2014; 4: 151-164
- A role for arginine-12 in thrombin-thrombomodulin-mediated activation of thrombin-activatable fibrinolysis inhibitor.J Thromb Haemost. 2014; 12: 1717-1725
- Mouse models of thrombosis: thrombomodulin.Thromb Haemost. 2004; 92: 467-477
- The first mutation identified in the thrombomodulin gene in a 45-year-old man presenting with thromboembolic disease.Blood. 1995; 85: 330-336
- Thrombomodulin with the Asp468Tyr mutation is expressed on the cell surface with normal cofactor activity for protein C activation.Br J Haematol. 1999; 106: 416-420
- Thrombomodulin gene defects in families with thromboembolic disease–a report on four families.Thromb Haemost. 1999; 81: 338-344
- Thrombomodulin gene variations and thromboembolic disease.Thromb Haemost. 1997; 78: 396-400
- A hereditary bleeding disorder resulting from a premature stop codon in thrombomodulin.Blood. 2014; 124 (p.Cys537Stop): 1951-1956
- A new pedigree with thrombomodulin-associated coagulopathy in which delayed fibrinolysis is partially attenuated by co-inherited TAFI deficiency.J Thromb Haemost. 2020; 18: 2209-2214
- Altered fibrinolysis in autosomal dominant thrombomodulin-associated coagulopathy.Blood. 2016; 128: 1879-1883
- A case of thrombomodulin mutation causing defective thrombin binding with absence of protein C and TAFI activation.Blood Adv. 2020; 4: 2631-2639
- Mice lacking the lectin-like domain of thrombomodulin are protected against melioidosis.Crit Care Med. 2014; 42: e221-e230
- The role of complement in Streptococcus pneumoniae-associated haemolytic uraemic syndrome.Nephrol Dial Transplant. 2013; 28: 2237-2245
- Mutations in alternative pathway complement proteins in American patients with atypical hemolytic uremic syndrome.Hum Mutat. 2010; 31: E1445-E1460
- Thrombomodulin mutations in atypical hemolytic-uremic syndrome.N Engl J Med. 2009; 361: 345-357
- A mutation in the thrombomodulin gene, 127G to A coding for Ala25Thr, and the risk of myocardial infarction in men.Thromb Haemost. 1998; 80: 743-748
- Activated protein C inhibits high mobility group box 1 signaling in endothelial cells.Blood. 2011; 118: 3952-3959
- Soluble thrombomodulin as a predictor of incident coronary heart disease and symptomless carotid artery atherosclerosis in the Atherosclerosis Risk in Communities (ARIC) Study: a case-cohort study.Lancet. 1999; 353: 1729-1734
- Coagulation phenotypes in sepsis and effects of recombinant human thrombomodulin: an analysis of three multicentre observational studies.Crit Care. 2021; 25: 114
Article info
Publication history
Published online: July 31, 2022
Accepted:
July 22,
2022
Received in revised form:
July 13,
2022
Received:
May 17,
2022
Identification
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