The factor V east Texas bleeding disorder (FVETBD) is caused by increased plasma tissue factor pathway inhibitor-? (TFPI?) concentration. The underlying cause is a variant in F5 causing alternative splicing within exon 13 and producing FV-short, which tightly binds the C-terminus of TFPI?, prolonging its circulatory half-life.Objectives
To diagnose a family presenting with variable bleeding and laboratory phenotypes.Patients/Methods
Samples were obtained from 17 family members for F5 exon 13 sequencing. Plasma/platelet TFPI and platelet FV were measured by ELISA and/or Western blot. Plasma thrombin generation potential was evaluated using calibrated automated thrombography.Results
The FVET variant was identified in all family members with bleeding symptoms and associated with elevated plasma TFPI? (4.5- to 13.4-fold) and total TFPI (2- to 3-fold). However, TFPI? and FV-short were not elevated in platelets. TF-initiated thrombin generation in patient plasma was diminished but was restored by a monoclonal anti-TFPI antibody or factor VIIa. TFPI? localized within vascular extracellular matrix in an oral lesion biopsy from an affected family member.Conclusions
FVETBD was diagnosed in an extended family. The variant was autosomal dominant and highly penetrant. Elevated plasma TFPI?, rather than platelet TFPI?, was likely the primary cause of bleeding. Plasma FV-short did not deplete TFPI? from extracellular matrix. In vitro thrombin generation was restored with an anti-TFPI antibody or factor VIIa suggesting effective therapies may be available. Increased awareness of, and testing for, bleeding disorders associated with F5 exon 13 variants and elevated plasma TFPI are needed.