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

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-α (TFPIα), resulting in an approximately 10-fold increase in plasma TFPIα, suggesting that the TFPIα:FV-short complexes are retained in circulation. The TFPIα: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 TFPIα:FV-short complex, which inhibits activation and propagation of coagulation.

• Authors: Lisa M Vincent, Sinh Tran, Ruzica Livaja, Tracy A Bensend, Dianna M Milewicz, Björn Dahlbäck
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 123 Issue 9 Pg. 3777-87 (Sep 2013) ISSN: 1558-8238 [Electronic] United States
• PMID: 23979162 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Lipoproteins
• Protein Isoforms
• lipoprotein-associated coagulation inhibitor
• Factor V

Topics

• Base Sequence
• Binding, Competitive
• Blood Coagulation
• Blood Coagulation Disorders, Inherited (genetics)
• DNA Mutational Analysis
• Factor V (genetics, metabolism)
• Genetic Association Studies
• Hemorrhagic Disorders (genetics)
• Humans
• Lipoproteins (blood)
• Molecular Sequence Data
• Point Mutation
• Protein Binding
• Protein Isoforms (blood)