Altered fibrinolysis in autosomal dominant thrombomodulin-associated coagulopathy.
Blood
; 128(14): 1879-1883, 2016 10 06.
Article
en En
| MEDLINE
| ID: mdl-27436851
ABSTRACT
Thrombomodulin-associated coagulopathy (TM-AC) is a newly recognized dominant bleeding disorder in which a p.Cys537Stop variant in the thrombomodulin (TM) gene THBD, results in high plasma TM levels and protein C-mediated suppression of thrombin generation. Thrombin in complex with TM also activates thrombin-activatable fibrinolysis inhibitor (TAFI). However, the effect of the high plasma TM on fibrinolysis in TM-AC is unknown. Plasma from TM-AC cases and high-TM model control samples spiked with recombinant soluble TM showed reduced tissue factor-induced thrombin generation. Lysis of plasma clots from TM-AC cases was significantly delayed compared with controls but was completely restored when TM/thrombin-mediated TAFI activation was inhibited. Clots formed in blood from TM-AC cases had the same viscoelastic strength as controls but also showed a TAFI-dependent delay in fibrinolysis. Delayed fibrinolysis was reproduced in high-TM model plasma and blood samples. Partial restoration of thrombin generation with recombinant activated factor VII or activated prothrombin complex concentrate did not alter the delayed fibrinolysis in high-TM model blood. Our finding of a previously unrecognized fibrinolytic phenotype indicates that bleeding in TM-AC has a complex pathogenesis and highlights the pivotal role of TM as a regulator of hemostasis.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Trastornos de la Coagulación Sanguínea
/
Trombomodulina
/
Fibrinólisis
Tipo de estudio:
Prognostic_studies
/
Risk_factors_studies
Límite:
Adult
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Female
/
Humans
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Male
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Middle aged
Idioma:
En
Revista:
Blood
Año:
2016
Tipo del documento:
Article
País de afiliación:
Reino Unido