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Coagulation factor ...
Coagulation factor V-A2440G causes east Texas bleeding disorder via TFPI alpha
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Vincent, Lisa M. (author)
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- Tran, Sinh (author)
- Lund University,Lunds universitet,Klinisk kemi, Malmö,Forskargrupper vid Lunds universitet,Clinical Chemistry, Malmö,Lund University Research Groups
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- Livaja Koshiar, Ruzica (author)
- Lund University,Lunds universitet,Klinisk kemi, Malmö,Forskargrupper vid Lunds universitet,Clinical Chemistry, Malmö,Lund University Research Groups
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Bensend, Tracy A. (author)
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Milewicz, Dianna M. (author)
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- Dahlbäck, Björn (author)
- Lund University,Lunds universitet,Klinisk kemi, Malmö,Forskargrupper vid Lunds universitet,Clinical Chemistry, Malmö,Lund University Research Groups
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(creator_code:org_t)
- 2013
- 2013
- English.
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In: Journal of Clinical Investigation. - 0021-9738. ; 123:9, s. 3777-3787
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Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medicinal Chemistry (hsv//eng)
Publication and Content Type
- art (subject category)
- ref (subject category)
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