Coagulation factor V(A2440G) causes east Texas bleeding disorder via TFPI?.

ABSTRACT: The autosomal dominantly inherited east Texas bleeding disorder is linked to an A2440G variant in exon 13 of the F5 gene. Affected individuals have normal levels of coagulation factor V (FV) activity, but demonstrate inhibition of global coagulation tests. We demonstrated that the A2440G mutation causes upregulation of an alternatively spliced F5 transcript that results in an in-frame deletion of 702 amino acids of the large activation fragment, the B domain. The approximately 250-kDa FV isoform (FV-short), which can be fully activated by thrombin, is present in all A2440G carriers' plasma (n = 16). FV-short inhibits coagulation through an indirect mechanism by forming a complex with tissue factor pathway inhibitor-? (TFPI?), resulting in an approximately 10-fold increase in plasma TFPI?, suggesting that the TFPI?:FV-short complexes are retained in circulation. The TFPI?:FV-short complexes efficiently inhibit thrombin generation of both intrinsic and extrinsic coagulation pathways. These data demonstrate that the east Texas bleeding disorder-associated F5(A2440G) leads to the formation of the TFPI?:FV-short complex, which inhibits activation and propagation of coagulation.

SUBMITTER: Vincent LM 

PROVIDER: S-EPMC3754264 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature