Increased thrombosis susceptibility and altered fibrin formation in STAT5-deficient mice.
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.
Nordstrom
Sarah M
SM
Cardiovascular Research Institute, University of California, San Francisco, CA, USA.
Holliday
Brian A
BA
Sos
Brandon C
BC
Smyth
James W
JW
Levy
Robert E
RE
Dukes
Jonathan W
JW
Lord
Susan T
ST
Weiss
Ethan J
EJ
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
D050799:STAT5 Transcription Factor; D005345:Fibrinopeptide B; D005337:Fibrin; D005176:Factor XIII
Proc Natl Acad Sci U S A. 1983 Dec;80(23):7318-22
6580646
Proc Natl Acad Sci U S A. 1997 Jul 8;94(14):7239-44
9207075
Oncogene. 1998 Jan 29;16(4):505-15
9484840
Science. 1986 Apr 25;232(4749):511-2
3008329
Blood. 2002 Nov 1;100(9):3240-4
12384423
Circulation. 2001 Feb 6;103(5):718-23
11156884
Cell Mol Life Sci. 2004 Apr;61(7-8):843-56
15095007
J Interferon Cytokine Res. 2003 May;23(5):229-35
12804065
Annu Rev Physiol. 1985;47:483-99
3888078
Endocrinology. 2007 May;148(5):1977-86
17317776
Mol Endocrinol. 2006 Jun;20(6):1333-51
16469768
Blood. 2004 Jan 15;103(2):594-600
12969982
Biochemistry. 1996 Feb 20;35(7):2342-8
8652575
J Biol Chem. 1999 Dec 10;274(50):35331-6
10585399
Haematologica. 2007 Feb;92(2):e17-9
17405747
Endocrinology. 2001 Sep;142(9):3836-41
11517160
Ann Clin Biochem. 1992 May;29 ( Pt 3):345-6
1610110
J Exp Med. 2009 Apr 13;206(4):819-31
19332876
J Hered. 1976 Mar-Apr;67(2):87-91
1270792
Arterioscler Thromb Vasc Biol. 1999 Aug;19(8):2012-6
10446086
Nature. 1993 Jul 15;364(6434):208-13
8391647
J Biol Chem. 2001 Apr 27;276(17):13817-21
11145969
Hepatology. 2007 Aug;46(2):504-13
17640041
Blood. 1991 May 1;77(9):1958-63
2018836
Methods Enzymol. 1993;222:341-58
8412803
Thromb Res. 1992 Sep 1;67(5):613-8
1448793
J Biol Chem. 2006 Dec 15;281(50):38208-16
17046817
J Clin Invest. 2008 Aug;118(8):2969-78
18618017
Biochem J. 2000 Feb 1;345 Pt 3:759-66
10642538
Endocr Rev. 1985 Spring;6(2):128-50
2861084
Oncogene. 2004 Oct 18;23(48):8017-23
15489919
J Mammary Gland Biol Neoplasia. 2008 Mar;13(1):93-103
18228120
J Biol Chem. 1995 Dec 8;270(49):29392-9
7493975
J Biol Chem. 2007 Jan 5;282(1):710-20
17090548
Blood. 1996 Nov 1;88(9):3432-45
8896408
Cell. 1998 May 29;93(5):841-50
9630227
J Clin Endocrinol Metab. 1998 Jul;83(7):2532-8
9661639
Br J Haematol. 1991 Oct;79(2):296-301
1958489