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

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

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)

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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 haemostasis 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 harboured 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
Number of pages6
JournalJournal of Thrombosis and Haemostasis
Early online date7 Jul 2020
DOIs
Publication statusE-pub ahead of print - 7 Jul 2020

Keywords

  • thrombomodulin
  • bleeding
  • fibrinolysis
  • genomics
  • TAFI (carboxypeptidase B2 (CPB2)/procarboxypeptidase U (proCPU))

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    Westbury, S. K., Whyte, C. S., Stephens, J., Downes, K., Turro, E., Claesen, K., Mertens, J., Hendriks, D., Latif, A-L., Leishman, E., NIHR BioResource, Mutch, N. J., Tait, C. 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. https://doi.org/10.1111/jth.14990