Hormones, age, and sex affect platelet responsiveness in vitro

Abstract

Background: Female sex confers a survival advantage following severe injury in the setting of trauma-induced coagulopathy, with female platelets having heightened responsiveness likely due to estrogen. The effects of testosterone on platelet biology are unknown, and platelets express both estradiol and androgen receptors on the plasma membrane. We hypothesize testosterone decreases platelet responses in vitro, and there are baseline differences in platelet function and metabolism stratified by sex/age. Study Design and Methods: Apheresis platelets were collected from: older males (OM) ≥45 years, younger males (YM) <45 years, older females (OF) ≥54 years, and younger females (YF) <54 years, and testosterone and estradiol were measured. Platelets were incubated with testosterone (5.31 ng/ml), estradiol (105 pg/ml) or vehicle and stimulated with buffer, adenosine diphosphate (20 μM), platelet activating factor (2 μM), or thrombin (0.3 U/ml). Aggregation, CD62P surface expression, fibrinogen receptor surface expression, and platelet mitochondrial metabolism were measured.Results: Testosterone significantly inhibited aggregation in OF and OM (p < .05), inhibited CD41a expression in YF, YM, and OM (p < .05), and affected a few of the baseline amounts of CD62P surface expression but not platelet activation to platelet-activating factor and adenosine diphosphate, and variably changed platelet metabolism.Discussion: Platelets have sex-and age-specific aggregation, receptor expression, and metabolism. Testosterone decreases platelet function dependent on the stimulus, age, and sex. Similarly, platelet metabolism has varying responses to sex hormones with baseline metabolic differences dependent upon sex and age.

Omics markers of platelet transfusion in trauma patients

“…Only apheresis PLTs were transfused in this study, so the impact of buffy coat PLTs 46,47 or other products (e.g., pathogen-inactivated PLTs 68 and cold-stored PLTs 48,69 ) remains to be assessed. In this study, we did not have access to samples from the transfused units nor to data on PLT storage duration or donor biology, such as age 29 and sex, 70,71 both factors impacting the omics phenotypes of PLTs at the time of donation as well as their functional activation profiles. Our results not only show feasibility of functional multi-omics studies at the interface of transfusion and critical care medicine but also provide interesting results showing an impact of PLT transfusion on molecular pathways critical to PLT function, coagulation cascades, and inflammation.…”

A pilot study of the metabolic profiles of apheresis platelets modified by donor age and sex and in vitro short‐term incubation with sex hormones

“…The platelet samples used for this study were the largest by volume so that the metabolomic differences could be assessed. 20 Elevated levels of free fatty acids have potential implications for platelet function, not just because fatty acid oxidation is coupled to platelet activation, 18,37 but also because of the direct platelet-activating function of arachidonic acid and its oxidation products. 38 Similarly, elevated levels of free amino acids have potential functional implications, especially when focusing on elevated levels of tryptophan and its catabolites through the kynurenine pathway in platelets from OM donors.…”

“…Lastly, the platelet concentrates used were part of a larger study that assessed the differences in sex and age with respect to both platelet function and mitochondrial metabolism. The platelet samples used for this study were the largest by volume so that the metabolomic differences could be assessed 20 …”

“…with estradiol, we investigated the possible alteration of mitochondrial, metabolism in response to short-term incubations with sex hormones. 2,3,20 Thus, we hypothesized that platelets from males and females have different metabolomic profiles, which may be altered by in vitro treatment with sex hormones and by donor age.…”

“…This is relevant in that, even though mature platelets lack nuclei, they express sex hormone receptors on the cellular membrane, and the effects of sex hormones on platelet function and specifically metabolite concentrations have not been well characterized 8 . In addition, because (1) females have decreased mortality following severe injury, (2) platelets from female donors have increased aggregation and functional properties (vs. platelets from male donors), and (3) some of these decreased functional properties of platelets from males may be reversed by in vitro incubation with estradiol, we investigated the possible alteration of mitochondrial, metabolism in response to short‐term incubations with sex hormones 2,3,20 . Thus, we hypothesized that platelets from males and females have different metabolomic profiles, which may be altered by in vitro treatment with sex hormones and by donor age.…”