Coagulation factor VA2440G causes east Texas bleeding disorder via TFPIα
Lisa M. Vincent, … , Dianna M. Milewicz, Björn Dahlbäck
Lisa M. Vincent, … , Dianna M. Milewicz, Björn Dahlbäck
Published August 27, 2013
Citation Information: J Clin Invest. 2013;123(9):3777-3787. https://doi.org/10.1172/JCI69091.
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Research Article

Coagulation factor VA2440G 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 F5A2440G 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

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Figure 4

TF-induced TGAs of plasma from affected and unaffected family members.

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TF-induced TGAs of plasma from affected and unaffected family members. I...
Individual thrombin generation curves are shown to the left. Affected family members are represented by solid lines, whereas the unaffected individuals are denoted with dotted lines. The affected individual with the highest thrombin generation was individual IV:17, who, in the Western blotting (Figure 1), demonstrated a weak FV-short band. The thrombin generation was monitored using fluorogenic substrate I-1140, the thrombin concentration given as Δ FU/ml (FU, fluorescence units). The right part of the figure demonstrates the thrombin generation using mixtures of affected and unaffected pooled plasma.