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 4

Procoagulant factor activity levels are higher in male than female mice and are GH dependent.

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pGH administration rescues the whole-blood clotting defect in lit mice a...
Blood was collected as in Figure 1. Coagulation factor activity assays were adapted for use in mice. (A) Plasma from 4 individual male and female mice was mixed with the indicated human factor–deficient plasma, and factor activity was normalized to that in WT B6 males and expressed as the mean (±SEM) percentage of male activity. Factor activity levels are greater in male versus female plasma for all assays (*P < 0.05, **P < 0.001; ANOVA with Bonferroni’s post-hoc test). (B) Plasma from 4 animals of each indicated group was collected and prepared and mean (±SEM) activity levels expressed as a percentage of male litm/+ –pGH activity. Factor activity levels were generally lower in female litm/+ –pGH and male and female litm/m –pGH mice versus male litm/+ –pGH and male and female litm/m +pGH for all assays. (C) The average of all procoagulant factor activity levels for each group. Factor activity levels were significantly lower in female litm/+ –pGH and male and female litm/m –pGH versus male litm/+ –pGH and male and female litm/m +pGH. **P < 0.01, ***P < 0.0001; ANOVA with Bonferroni’s post-hoc test.