Background: The FV east Texas (FVET) bleeding disorder produces a 5- to 10-fold increase in the Tissue Factor Pathway Inhibitor-alpha (TFPIα) plasma concentration. It is caused by a FV B-domain mutation producing FVshort. The TFPIα C-terminus has homology with the FV B-domain basic region and tightly binds the FVshort B-domain acidic region in FVET patients. The rapid inhibition of prothrombinase by TFPIα bound to FVshort may be the primary anticoagulant mechanism causing bleeding in FVET patients. 

Aims: Characterize three generations of an extended family who presented with variable bleeding and laboratory phenotypes.

Methods: Plasma TFPIα was measured by ELISA, Western blot, and calibrated automated thrombography. The FV B-domain was sequenced.

Results: Over 13 years, a proband (male) presented with undiagnosed mild mucocutaneous bleeding symptoms, and significant post-surgical and post-traumatic hemorrhage, treated with rFVIIa due to failure of universal hemostatic agents including DDAVP and antifibrinolytics. Similar bleeding was present in eight family members across three generations. The only abnormality in the hemostatic evaluation of the proband and some symptomatic family members was variably prolonged PT and aPTT tests. The proband and all symptomatic family members carried the FVET mutation, indicating complete penetrance of the mutation, and had 5- to 10-fold elevated plasma TFPIα. Thrombin generation in patient plasma was undetectable in reactions initiated with 1 pM TF but was restored to normal upon addition of a monoclonal antibody specific for the K2 domain of TFPI.

Conclusions: The FVET bleeding disorder was diagnosed in an extended Indiana family, genetically unlinked to the original east Texas pedigree. Evaluation of rare bleeding disorders should include measurement of plasma TFPIα and DNA sequencing of FV B-domain. In vitro thrombin generation assays suggest that antibodies directed against the TFPI K2 domain, which are in development for hemophilia prophylaxis, may be therapeutically effective in FVET patients or others with mutations producing FVshort.

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/the-fv-east-texas-variant-causes-bleeding-in-a-three-generation-family-from-indiana/