A hereditary bleeding disorder resulting from a premature stop codon in thrombomodulin (p.Cys537Stop).
Blood
; 124(12): 1951-6, 2014 Sep 18.
Article
en En
| MEDLINE
| ID: mdl-25049278
ABSTRACT
In this study, we describe a novel thrombomodulin (TM) mutation (c.1611C>A) that codes for a change from cysteine 537 to a premature stop codon (p.Cys537Stop). Three members of a family with a history of posttraumatic bleeding were identified to be heterozygous for this TM mutation. All coagulation screening tests, coagulation factor assays, and platelet function test results were within normal limits. However, the endogenous thrombin potential was markedly reduced at low-tissue factor concentration, and failure to correct with normal plasma indicated the presence of a coagulation inhibitor. Plasma TM levels were highly elevated (433-845 ng/ml, normal range 2-8 ng/ml, equating to 5 to 10 nM), and the addition of exogenous protein C further decreased thrombin generation. The mutation, p.Cys537Stop, results in a truncation within the carboxyl-terminal transmembrane helix. We predict that as a consequence of the truncation, the variant TM is shed from the endothelial surface into the blood plasma. This would promote systemic protein C activation and early cessation of thrombin generation within a developing hemostatic clot, thereby explaining the phenotype of posttraumatic bleeding observed within this family.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Trombomodulina
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Codón sin Sentido
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Trastornos de la Coagulación Sanguínea Heredados
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Proteínas Mutantes
Tipo de estudio:
Prognostic_studies
Límite:
Adult
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Female
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Humans
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Male
Idioma:
En
Revista:
Blood
Año:
2014
Tipo del documento:
Article