title: A hereditary bleeding disorder resulting from a premature stop codon in thrombomodulin (p.Cys537Stop).
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.
authors: Cambridge Haemophilia and Thrombophilia Centre, Addenbrooke's Hospital, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge, United Kingdom; and.
authors: Jonathan
authors: J
authors: Langdown
authors: Cambridge Haemophilia and Thrombophilia Centre, Addenbrooke's Hospital, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge, United Kingdom; and.
authors: Roger J
authors: RJ
authors: Luddington
authors: University of Cambridge, Department of Haematology, Cambridge Institute for Medical Research, Cambridge, United Kingdom.
authors: James A
authors: JA
authors: Huntington
authors: Cambridge Haemophilia and Thrombophilia Centre, Addenbrooke's Hospital, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge, United Kingdom; and.
authors: Trevor P
authors: http://orcid.org/0000-0002-5181-2047
authors: TP
authors: Baglin
mesh_terms: D000328:Adult; D025861:Blood Coagulation Disorders, Inherited / Q000097:blood / Q000235:genetics* / Q000628:therapy; D001779:Blood Coagulation Factors / Q000627:therapeutic use; D001780:Blood Coagulation Tests; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D050505:Mutant Proteins / Q000097:blood / Q000737:chemistry / Q000235:genetics*; D016035:Pancreas Transplantation; D017434:Protein Structure, Tertiary; D018180:Thrombomodulin / Q000097:blood / Q000737:chemistry / Q000235:genetics*
chemical_list: D001779:Blood Coagulation Factors; D018389:Codon, Nonsense; D050505:Mutant Proteins; C546931:THBD protein, human; D018180:Thrombomodulin; C025667:prothrombin complex concentrates