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- Vincent, Lisa M., et al.
(author)
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Coagulation factor V-A2440G causes east Texas bleeding disorder via TFPI alpha
- 2013
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In: Journal of Clinical Investigation. - 0021-9738. ; 123:9, s. 3777-3787
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Journal article (peer-reviewed)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-alpha (TFPI alpha), resulting in an approximately 10-fold increase in plasma TFPI alpha, suggesting that the TFPI alpha:FV-short complexes are retained in circulation. The TFPI alpha: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 alpha:FV-short complex, which inhibits activation and propagation of coagulation.
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