Abstract Number: PB1203
Meeting: ISTH 2020 Congress
Theme: Hemophilia and Rare Bleeding Disorders » Rare Bleeding Disorders
Background: Thrombomodulin (TM) regulates coagulation and fibrinolysis by interaction with thrombin promoting activation of Protein C and thrombin activatable fibrinolysis inhibitor (TAFI, also denoted procarboxypeptidase U). Familial cases of TM-associated coagulopathy have been described displaying augmented plasma TM levels due to a premature stop codon in THBD (p.Cys537stop).
Aims: To investigate the impact of a novel THBD variant (THBD: c.1487delC, p.Pro496Argfs*10) on coagulation and fibrinolysis parameters in a family with 4 affected individuals.
Methods: The index case presented with ´unexplained bleeding´ and abnormal prothrombin consumption index. Family members, recruited to NIHR BioResource, were analysed by ThromboGenomics (panel v2.8) and Sanger sequencing. Plasma levels of TM, TAFI and endogenous thrombin potential were determined by ELISA, activity assay and calibrated automated thrombography respectively. Plasma clot lysis rates were determined by turbidity assay ± carboxypeptidase inhibitor (CPI).
Results: THBD p.Pro496Argfs*10 cases reported excessive bleeding (median ISTH BAT score 6). TM plasma levels were significantly elevated (median 556 ng/ml, normal 2.9-7.6 ng/ml). The presence of the THBD p.Pro496Argfs*10 attenuated the endogenous thrombin potential and delayed clot lysis. Inhibition of TAFIa by CPI reduced the prolongation of lysis. Two affected individuals and one additional family member were found to harbour a monoallelic high impact variant in the TAFI gene (CPB2 p.Arg114*). Individuals with the CPB2 p.Arg114* variant exhibited low plasma TAFI levels (median 542 U/L, normal 677-1309 U/L). Coinheritance of CPB2 p.Arg114*with THBD p.Pro496Argfs*10 diminished the impact of the TM mutation on lysis. In contrast, the individual with only the CPB2 p.Arg114* variant showed enhanced lysis compared to control.
Conclusions: The novel THBD variant, THBD p.Pro496Argfs*10 gives rise to marked elevation of plasma TM levels. The functional consequences are enhanced potential for thrombin generation and TM-mediated TAFI activation. Coinheritance of CPB2 p.Arg114* results in an intermediate fibrinolytic profile highlighting the complexities of independently inherited variants on pathogenesis of mild coagulopathies.
To cite this abstract in AMA style:
Whyte CS, Westbury S, Tait RC, Mutch NJ, Downes K, Mertens J, Claesen K, Hendriks D, Leishman E, Mumford A, NIHR BioResource . Fibrinolytic Alterations in a Thrombomodulin-associated Coagulopathy Are Diminished by Coinheritance of a TAFI Mutation [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/fibrinolytic-alterations-in-a-thrombomodulin-associated-coagulopathy-are-diminished-by-coinheritance-of-a-tafi-mutation/. Accessed December 2, 2022.« Back to ISTH 2020 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/fibrinolytic-alterations-in-a-thrombomodulin-associated-coagulopathy-are-diminished-by-coinheritance-of-a-tafi-mutation/