Sex differences in thrombosis in mice are mediated by sex-specific growth hormone secretion patterns
Joshua H. Wong, … , Tina S. Fong, Ethan J. Weiss
Joshua H. Wong, … , Tina S. Fong, Ethan J. Weiss
Published July 10, 2008
Citation Information: J Clin Invest. 2008;118(8):2969-2978. https://doi.org/10.1172/JCI34957.
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Research Article Hematology

Sex differences in thrombosis in mice are mediated by sex-specific growth hormone secretion patterns

Abstract

Sex differences in thrombosis are well described, but their underlying mechanism(s) are not completely understood. Coagulation proteins are synthesized in the liver, and liver gene expression is sex specific and depends on sex differences in growth hormone (GH) secretion — males secrete GH in a pulsatile fashion, while females secrete GH continuously. Accordingly, we tested the hypothesis that sex-specific GH secretion patterns cause sex differences in thrombosis. Male mice were more susceptible to thrombosis than females in the thromboplastin-induced pulmonary embolism model and showed shorter clotting times ex vivo. GH-deficient little (lit) mice were protected from thrombosis, and pulsatile GH given to lit mice restored the male clotting phenotype. Moreover, pulsatile GH administration resulted in a male clotting phenotype in control female mice, while continuous GH caused a female clotting phenotype in control male mice. Expression of the coagulation inhibitors Proc, Serpinc1, Serpind1, and Serpina5 were strongly modulated by sex-specific GH patterns, and GH modulated resistance to activated protein C. These results reveal what we believe to be a novel mechanism whereby sex-specific GH patterns mediate sex differences in thrombosis through coordinated changes in the expression of coagulation inhibitor genes in the liver.

Authors

Joshua H. Wong, Jonathan Dukes, Robert E. Levy, Brandon Sos, Sara E. Mason, Tina S. Fong, Ethan J. Weiss

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Figure 1

Sex differences in thrombosis in WT mice.

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Sex differences in thrombosis in WT mice. Blood was drawn from 15 male a...
Blood was drawn from 15 male and female WT B6 mice. (A) Mean whole-blood clotting times were significantly shorter in male versus female mice. P < 0.0001, Student’s t test. (B) Whole-blood clotting was triggered with 2 dilutions (indicated) of thromboplastin. The reaction was quenched at 5-minute intervals, and thrombin-antithrombin (TAT) levels were measured. For the 1:1,000 dilution, TAT values (±SEM) were higher in male versus female mice at all time points. For the 1:100,000 dilution, TAT was higher in males at the 15- and 20-minute time points (**P < 0.01, ***P < 0.001; ANOVA with Bonferroni’s post-hoc test). Data represent pooled blood from 5 mice of each sex each run in duplicate and measured in duplicate. (C) The indicated numbers of male and female WT mice were injected with 2 μl/g of a 1:160 dilution of thromboplastin in the in vivo model of PE. Data are presented as percent survival, which was greater in female versus male mice as compared by the log-rank test (P = 0.01).