Coagulation factor V-A2440G causes east Texas bleeding disorder via TFPI alpha
(2013) In Journal of Clinical Investigation 123(9). p.3777-3787- 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),... (More)
- 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. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/4101982
- author
- Vincent, Lisa M. ; Tran, Sinh LU ; Livaja Koshiar, Ruzica LU ; Bensend, Tracy A. ; Milewicz, Dianna M. and Dahlbäck, Björn LU
- organization
- publishing date
- 2013
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Clinical Investigation
- volume
- 123
- issue
- 9
- pages
- 3777 - 3787
- publisher
- The American Society for Clinical Investigation
- external identifiers
-
- wos:000324562600023
- scopus:84883543544
- pmid:23979162
- ISSN
- 0021-9738
- DOI
- 10.1172/JCI69091
- language
- English
- LU publication?
- yes
- id
- dc904ca7-8ee4-4020-b68a-37394302eca4 (old id 4101982)
- date added to LUP
- 2016-04-01 14:12:11
- date last changed
- 2022-04-22 01:56:04
@article{dc904ca7-8ee4-4020-b68a-37394302eca4,
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.}},
author = {{Vincent, Lisa M. and Tran, Sinh and Livaja Koshiar, Ruzica and Bensend, Tracy A. and Milewicz, Dianna M. and Dahlbäck, Björn}},
issn = {{0021-9738}},
language = {{eng}},
number = {{9}},
pages = {{3777--3787}},
publisher = {{The American Society for Clinical Investigation}},
series = {{Journal of Clinical Investigation}},
title = {{Coagulation factor V-A2440G causes east Texas bleeding disorder via TFPI alpha}},
url = {{https://lup.lub.lu.se/search/files/3841869/4175220.pdf}},
doi = {{10.1172/JCI69091}},
volume = {{123}},
year = {{2013}},
}