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 language | English |
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Pages (from-to) | 2209-2214 |
Number of pages | 6 |
Journal | Journal of Thrombosis and Haemostasis |
Volume | 18 |
Issue number | 9 |
Early online date | 23 Jul 2020 |
DOIs | |
Publication status | Published - 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]