A new pedigree with thrombomodulin-associated coagulopathy in which delayed fibrinolysis is partially attenuated by co-inherited TAFI deficiency

Sarah K. Westbury* (Corresponding Author), Claire S. Whyte, Jonathan Stephens, Kate Downes, Ernest Turro, Karen Claesen, Joachim C Mertens, Dirk Hendriks, Anne‐Louise Latif, Emma J Leishman, NIHR BioResource, Nicola J. Mutch, R. Campbell Tait, Andrew D. Mumford

*Corresponding author for this work

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Background: Thrombomodulin-associated coagulopathy (TM-AC) is a rare bleeding disorder in which a single reported p.Cys537* variant in the thrombomodulin gene THBD causes high plasma thrombomodulin (TM) levels. High TM levels attenuate thrombin generation and delay fibrinolysis. Objectives: To report the characteristics of pedigree with a novel THBD variant causing TM-AC, and co-inherited deficiency of thrombin-activatable fibrinolysis inhibitor (TAFI). Patients/methods: Identification of pathogenic variants in hemostasis genes by next-generation sequencing and case recall for deep phenotyping. Results: Pedigree members with a previously reported THBD variant predicting p.Pro496Argfs*10 and chain truncation in TM transmembrane domain had abnormal bleeding and greatly increased plasma TM levels. Affected cases had attenuated thrombin generation and delayed fibrinolysis similar to previous reported TM_AC cases with THBD p.Cys537*. Coincidentally, some pedigree members also harbored a stop-gain variant in CPB2 encoding TAFI. This reduced plasma TAFI levels but was asymptomatic. Pedigree members with TM-AC caused by the p.Pro496Argfs*10 THBD variant and also TAFI deficiency had a partially attenuated delay in fibrinolysis, but no change in the defective thrombin generation. Conclusions: These data extend the reported genetic repertoire of TM-AC and establish a common molecular pathogenesis arising from high plasma levels of TM extra-cellular domain. The data further confirm that the delay in fibrinolysis associated with TM-AC is directly linked to increased TAFI activation. The combination of the rare variants in the pedigree members provides a unique genetic model to develop understanding of the thrombin-TM system and its regulation of TAFI.

Original languageEnglish
Pages (from-to)2209-2214
Number of pages6
JournalJournal of Thrombosis and Haemostasis
Volume18
Issue number9
Early online date23 Jul 2020
DOIs
Publication statusPublished - Sep 2020

Keywords

  • Thrombomodulin
  • Bleeding
  • Fibrinolysis
  • Genomics
  • TAFI (carboxypeptidase B2 (CPB2)/procarboxypeptidase U (proCPU))
  • fibrinolysis
  • bleeding
  • thrombomodulin
  • genomics
  • TAFI (carboxypeptidase B2 [CPB2]/procarboxypeptidase U [proCPU])
  • LYSIS
  • procarboxypeptidase U [proCPU])
  • DISORDER
  • TAFI (carboxypeptidase B2 [CPB2]

Fingerprint Dive into the research topics of 'A new pedigree with thrombomodulin-associated coagulopathy in which delayed fibrinolysis is partially attenuated by co-inherited TAFI deficiency'. Together they form a unique fingerprint.

  • Cite this

    Westbury, S. K., Whyte, C. S., Stephens, J., Downes, K., Turro, E., Claesen, K., Mertens, J. C., Hendriks, D., Latif, AL., Leishman, E. J., NIHR BioResource, Mutch, N. J., Campbell Tait, R., & Mumford, A. D. (2020). A new pedigree with thrombomodulin-associated coagulopathy in which delayed fibrinolysis is partially attenuated by co-inherited TAFI deficiency. Journal of Thrombosis and Haemostasis, 18(9), 2209-2214. https://doi.org/10.1111/jth.14990