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 journalArticlepeer-review

8 Citations (Scopus)


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
Issue number9
Early online date23 Jul 2020
Publication statusPublished - Sep 2020


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


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