Coagulation factor V-A2440G causes east Texas bleeding disorder via TFPI alpha

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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.

Detaljer

Författare
  • Lisa M. Vincent
  • Sinh Tran
  • Ruzica Livaja Koshiar
  • Tracy A. Bensend
  • Dianna M. Milewicz
  • Björn Dahlbäck
Enheter & grupper
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Läkemedelskemi
Originalspråkengelska
Sidor (från-till)3777-3787
TidskriftJournal of Clinical Investigation
Volym123
Utgivningsnummer9
StatusPublished - 2013
PublikationskategoriForskning
Peer review utfördJa

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