Female platelets have distinct functional activity compared with male platelets: Implications in transfusion practice and treatment of trauma-induced coagulopathy

Abstract

BACKGROUND Females are hypercoagulable and have survival benefit in trauma-induced coagulopathy (TIC). The mechanism for this sex-specific hypercoagulability is unknown. Platelets and platelet function are central in providing hemostatic potential and are the largest contributor to clot strength. Ligands (adenosine diphosphate [ADP] and platelet-activating factor [PAF]) bind distinct platelet receptors to potentiate activation and aggregation. We hypothesize that female platelets have a differential response to ADP and PAF, resulting in greater aggregation and activation compared to males, and that estradiol pretreatment of male or female platelets enhances this activity. METHODS Platelets were collected from healthy volunteers: premenopausal/postmenopausal females (≤54 years, >54 years) and similarly aged males. Platelet aggregometry and flow cytometry (fibrinogen binding capacity) were examined. After treatment with ADP or PAF, platelet aggregation was assessed with Chronolog and activation assessed by CD41 receptor surface expression using flow cytometry. Aggregation and activation were again assessed after platelet pretreatment with estradiol. RESULTS Healthy volunteers included 12 premenopausal and 13 postmenopausal females and 18 similarly aged males. Female platelets (combined premenopausal and postmenopausal) had increased aggregation with ADP stimulation, as compared to male platelets. Male and female platelets had differential fibrinogen receptor expression, with female platelets (combined premenopausal and postmenopausal) demonstrating robust activation with ADP versus male platelets with PAF. In the presence of estradiol incubation, male platelets' activation with PAF approximated that of females (combined premenopausal and postmenopausal) and activation with PAF was enhanced in both male and female platelets. CONCLUSION Male and female platelets have differential response to stimuli, suggesting sex-dependent signaling and cellular activation. Female platelets have both increased aggregation and activation potential, and estradiol pretreatment feminizes male platelets to approximate female platelet activation with PAF. These findings offer potential explanation for sex-based differences in hemostatic potential in TIC and question whether donor sex of transfused platelets should be considered in resuscitation. Estradiol may also serve as a novel therapeutic adjunct in TIC.

Hypercoagulability in pregnant trauma patients

“…Additionally, estradiol pretreatment feminizes male platelets. 31 These hormonal effects may play a role in the performance of platelets in trauma-induced coagulopathy and may contribute to sex-specific outcomes in severe trauma.…”

Subchronic oral toxicity evaluation of gold nanoparticles in male and female mice

“…Male and female platelets have a differential response to ligand-induced activation, and female platelets show an increased activation potential. Male platelets pretreatment estradiol displayed approximate female platelet activation induced by platelet-activating factor [ 42 ]. A case-control study demonstrated women oral contraceptives increased the risk of venous thrombosis, and showed a positive association with oestrogen dose [ 43 ].…”

Traumatic-Induced Coagulopathy as a Systems Failure: A New Window into Hemostasis

“…56,57 Lastly, and of great clinical significance, Colman et al reported gender differences in TIC, with female platelets having increased aggregation and activation potential compared with platelets from males. 58 The authors further suggested that estradiol may serve as a possible therapeutic adjunct in treating eTIC. 58 These findings raise many new questions on the effect of gender on the relative contributions of platelets and fibrinogen to clot formation in trauma patients, which may be sought using a variety of methods including ROTEM, TEG, rapid-kinetic monitoring, X-ray crystallography, nuclear magnetic resonance, and electron microscopy.…”

“…58 The authors further suggested that estradiol may serve as a possible therapeutic adjunct in treating eTIC. 58 These findings raise many new questions on the effect of gender on the relative contributions of platelets and fibrinogen to clot formation in trauma patients, which may be sought using a variety of methods including ROTEM, TEG, rapid-kinetic monitoring, X-ray crystallography, nuclear magnetic resonance, and electron microscopy. [59][60][61] In the clinical environment, this new information may help guide which resuscitation protocol and blood product(s) is best suited for males and females following trauma.…”