title: Increased thrombosis susceptibility and altered fibrin formation in STAT5-deficient mice.
abstract: To explore the effect(s) of growth hormone signaling on thrombosis, we studied signal transduction and transcription factor 5 (STAT5)-deficient mice and found markedly reduced survival in an in vivo thrombosis model. These findings were not explained by a compensatory increase in growth hormone secretion. There was a modest increase in the activity of several procoagulant factors, but there was no difference in the rate or magnitude of thrombin generation in STAT5-deficient mice relative to control. However, thrombin-triggered clot times were markedly shorter, and fibrin polymerization occurred more rapidly in plasma from STAT5-deficient mice. Fibrinogen depletion and mixing studies indicated that the effect on fibrin polymerization was not due to intrinsic changes in fibrinogen, but resulted from changes in the concentration of a circulating plasma inhibitor. While thrombin-triggered clot times were significantly shorter in STAT5-deficient animals, reptilase-triggered clot times were unchanged. Accordingly, while the rate of thrombin-catalyzed release of fibrinopeptide A was similar, the release of fibrinopeptide B was accelerated in STAT5-deficient plasma versus control. Taken together, these studies demonstrated that the loss of STAT5 resulted in a decrease in the concentration of a plasma inhibitor affecting thrombin-triggered cleavage of fibrinopeptide B. This ultimately resulted in accelerated fibrin polymerization and greater thrombosis susceptibility in STAT5-deficient animals.
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, CA, USA.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Nordstrom
authors.forename: Brian A
authors.initials: BA
authors.lastname: Holliday
authors.forename: Brandon C
authors.initials: BC
authors.lastname: Sos
authors.forename: James W
authors.initials: JW
authors.lastname: Smyth
authors.forename: Robert E
authors.initials: RE
authors.lastname: Levy
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Dukes
authors.forename: Susan T
authors.initials: ST
authors.lastname: Lord
authors.forename: Ethan J
authors.initials: EJ
authors.lastname: Weiss
mesh_terms: D000818:Animals; D001777:Blood Coagulation; D004195:Disease Models, Animal; D005176:Factor XIII / Q000378:metabolism; D005337:Fibrin / Q000378:metabolism*; D005345:Fibrinopeptide B / Q000378:metabolism; D015151:Immunoblotting; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011655:Pulmonary Embolism / Q000378:metabolism* / Q000473:pathology; D050799:STAT5 Transcription Factor / Q000502:physiology*; D015398:Signal Transduction; D013918:Thrombin Time; D013927:Thrombosis / Q000378:metabolism* / Q000473:pathology
chemical_list: D050799:STAT5 Transcription Factor; D005345:Fibrinopeptide B; D005337:Fibrin; D005176:Factor XIII
references.citation: Proc Natl Acad Sci U S A. 1983 Dec;80(23):7318-22
references.pmid: 6580646
references.citation: Proc Natl Acad Sci U S A. 1997 Jul 8;94(14):7239-44
references.pmid: 9207075
references.citation: Oncogene. 1998 Jan 29;16(4):505-15
references.pmid: 9484840
references.citation: Science. 1986 Apr 25;232(4749):511-2
references.pmid: 3008329
references.citation: Blood. 2002 Nov 1;100(9):3240-4
references.pmid: 12384423
references.citation: Circulation. 2001 Feb 6;103(5):718-23
references.pmid: 11156884
references.citation: Cell Mol Life Sci. 2004 Apr;61(7-8):843-56
references.pmid: 15095007
references.citation: J Interferon Cytokine Res. 2003 May;23(5):229-35
references.pmid: 12804065
references.citation: Annu Rev Physiol. 1985;47:483-99
references.pmid: 3888078
references.citation: Endocrinology. 2007 May;148(5):1977-86
references.pmid: 17317776
references.citation: Mol Endocrinol. 2006 Jun;20(6):1333-51
references.pmid: 16469768
references.citation: Blood. 2004 Jan 15;103(2):594-600
references.pmid: 12969982
references.citation: Biochemistry. 1996 Feb 20;35(7):2342-8
references.pmid: 8652575
references.citation: J Biol Chem. 1999 Dec 10;274(50):35331-6
references.pmid: 10585399
references.citation: Haematologica. 2007 Feb;92(2):e17-9
references.pmid: 17405747
references.citation: Endocrinology. 2001 Sep;142(9):3836-41
references.pmid: 11517160
references.citation: Ann Clin Biochem. 1992 May;29 ( Pt 3):345-6
references.pmid: 1610110
references.citation: J Exp Med. 2009 Apr 13;206(4):819-31
references.pmid: 19332876
references.citation: J Hered. 1976 Mar-Apr;67(2):87-91
references.pmid: 1270792
references.citation: Arterioscler Thromb Vasc Biol. 1999 Aug;19(8):2012-6
references.pmid: 10446086
references.citation: Nature. 1993 Jul 15;364(6434):208-13
references.pmid: 8391647
references.citation: J Biol Chem. 2001 Apr 27;276(17):13817-21
references.pmid: 11145969
references.citation: Hepatology. 2007 Aug;46(2):504-13
references.pmid: 17640041
references.citation: Blood. 1991 May 1;77(9):1958-63
references.pmid: 2018836
references.citation: Methods Enzymol. 1993;222:341-58
references.pmid: 8412803
references.citation: Thromb Res. 1992 Sep 1;67(5):613-8
references.pmid: 1448793
references.citation: J Biol Chem. 2006 Dec 15;281(50):38208-16
references.pmid: 17046817
references.citation: J Clin Invest. 2008 Aug;118(8):2969-78
references.pmid: 18618017
references.citation: Biochem J. 2000 Feb 1;345 Pt 3:759-66
references.pmid: 10642538
references.citation: Endocr Rev. 1985 Spring;6(2):128-50
references.pmid: 2861084
references.citation: Oncogene. 2004 Oct 18;23(48):8017-23
references.pmid: 15489919
references.citation: J Mammary Gland Biol Neoplasia. 2008 Mar;13(1):93-103
references.pmid: 18228120
references.citation: J Biol Chem. 1995 Dec 8;270(49):29392-9
references.pmid: 7493975
references.citation: J Biol Chem. 2007 Jan 5;282(1):710-20
references.pmid: 17090548
references.citation: Blood. 1996 Nov 1;88(9):3432-45
references.pmid: 8896408
references.citation: Cell. 1998 May 29;93(5):841-50
references.pmid: 9630227
references.citation: J Clin Endocrinol Metab. 1998 Jul;83(7):2532-8
references.pmid: 9661639
references.citation: Br J Haematol. 1991 Oct;79(2):296-301
references.pmid: 1958489