title: Coagulation factor V(A2440G) 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 F5(A2440G) leads to the formation of the TFPIα:FV-short complex, which inhibits activation and propagation of coagulation.
authors: Department of Internal Medicine, Division of Medical Genetics, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
authors: Lisa M
authors: LM
authors: Vincent
authors: Sinh
authors: S
authors: Tran
authors: Ruzica
authors: R
authors: Livaja
authors: Tracy A
authors: TA
authors: Bensend
authors: Dianna M
authors: DM
authors: Milewicz
authors: Björn
authors: B
authors: Dahlbäck
mesh_terms: D001483:Base Sequence; D001667:Binding, Competitive; D001777:Blood Coagulation; D025861:Blood Coagulation Disorders, Inherited / Q000235:genetics*; D004252:DNA Mutational Analysis; D005165:Factor V / Q000235:genetics* / Q000378:metabolism; D056726:Genetic Association Studies; D006474:Hemorrhagic Disorders / Q000235:genetics*; D006801:Humans; D008074:Lipoproteins / Q000097:blood*; D008969:Molecular Sequence Data; D017354:Point Mutation; D011485:Protein Binding; D020033:Protein Isoforms / Q000097:blood
chemical_list: D008074:Lipoproteins; D020033:Protein Isoforms; C051928:lipoprotein-associated coagulation inhibitor; D005165:Factor V
references: J Biol Chem. 2008 Mar 14;283(11):6648-55
references: 18198180
references: J Thromb Haemost. 2009 Dec;7(12):1951-61
references: 19765210
references: Proc Natl Acad Sci U S A. 1994 Feb 15;91(4):1396-400
references: 8108421
references: Arterioscler Thromb Vasc Biol. 1997 Nov;17(11):2765-75
references: 9409254
references: Biochemistry. 1987 Oct 6;26(20):6508-14
references: 2827731
references: Proc Natl Acad Sci U S A. 1987 Jul;84(14):4846-50
references: 3110773
references: Blood. 1988 Mar;71(3):539-55
references: 3125864
references: Arterioscler Thromb Vasc Biol. 2002 Apr 1;22(4):530-8
references: 11950687
references: J Thromb Haemost. 2005 Mar;3(3):450-6
references: 15748232
references: J Biol Chem. 1979 Jan 25;254(2):508-17
references: 762076
references: Biochemistry. 1992 Apr 21;31(15):3777-85
references: 1567832
references: Blood. 1982 Jul;60(1):59-63
references: 7082847
references: Blood. 2008 Nov 1;112(9):3615-23
references: 18695002
references: Blood. 2002 Jul 15;100(2):524-30
references: 12091344
references: Blood. 2001 Mar 15;97(6):1549-54
references: 11238089
references: Blood. 2002 Jul 1;100(1):148-52
references: 12070020
references: Biochemistry. 1981 Jan 6;20(1):28-33
references: 7470475
references: Genome Res. 2004 Apr;14(4):708-15
references: 15060014
references: Blood. 2012 Feb 2;119(5):1256-62
references: 22144186
references: J Biol Chem. 2004 Nov 12;279(46):47528-35
references: 15337738
references: Front Biosci (Landmark Ed). 2012 Jan 01;17:262-80
references: 22201743
references: Biochemistry. 1994 Jun 7;33(22):6952-9
references: 8204629
references: Blood. 1991 Jun 15;77(12):2556-60
references: 2043761
references: J Biol Chem. 1981 Jan 25;256(2):1002-7
references: 7451453
references: Methods Enzymol. 1990;185:487-511
references: 2381327
references: Blood. 2008 Jul 1;112(1):19-27
references: 18574041
references: Blood. 2002 Feb 1;99(3):923-30
references: 11806995
references: Thromb Haemost. 2007 Sep;98(3):530-42
references: 17849041
references: J Biol Chem. 1984 Mar 10;259(5):3187-96
references: 6421819
references: Thromb Res. 2012 May;129 Suppl 2:S44-5
references: 22405586
references: Genomics. 1988 May;2(4):324-8
references: 3220473
references: Proc Natl Acad Sci U S A. 2006 Feb 28;103(9):3106-11
references: 16488980
references: J Biol Chem. 2012 Jul 27;287(31):26342-51
references: 22707727
references: J Biol Chem. 1994 Dec 16;269(50):31869-80
references: 7989361
references: J Biol Chem. 1995 Aug 18;270(33):19217-24
references: 7642592
references: J Thromb Haemost. 2012 Sep;10(9):1944-6
references: 22738072
references: J Biol Chem. 1994 Jun 24;269(25):17329-37
references: 8006042
references: J Biol Chem. 2002 May 24;277(21):18322-33
references: 11893748
references: Biochemistry. 1996 May 21;35(20):6450-9
references: 8639592
references: J Biol Chem. 1997 Aug 22;272(34):21527-33
references: 9261172
references: Thromb Diath Haemorrh. 1972 Jul 31;27(3):490-501
references: 4662612
references: J Biol Chem. 1982 Jun 10;257(11):6556-64
references: 7076681