The Human Endogenous Circadian System Causes Greatest Platelet Activation during the Biological Morning Independent of Behaviors
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BACKGROUND: Platelets are involved in the thromboses that are central to myocardial infarctions and ischemic strokes. Such adverse cardiovascular events have day/night patterns with peaks in the morning (~9 AM), potentially related to endogenous circadian clock control of platelet activation. The objective was to test if the human endogenous circadian system influences (1) platelet function and (2) platelet response to standardized behavioral stressors. We also aimed to compare the magnitude of any effects on platelet function caused by the circadian system with that caused by varied standardized behavioral stressors, including mental arithmetic, passive postural tilt and mild cycling exercise. METHODOLOGY/PRINCIPAL FINDINGS: We studied 12 healthy adults (6 female) who lived in individual laboratory suites in dim light for 240 h, with all behaviors scheduled on a 20-h recurring cycle to permit assessment of endogenous circadian function independent from environmental and behavioral effects including the sleep/wake cycle. Circadian phase was assessed from core body temperature. There were highly significant endogenous circadian rhythms in platelet surface activated glycoprotein (GP) IIb-IIIa, GPIb and P-selectin (6-17% peak-trough amplitudes; p ≤ 0.01). These circadian peaks occurred at a circadian phase corresponding to 8-9 AM. Platelet count, ATP release, aggregability, and plasma epinephrine also had significant circadian rhythms but with later peaks (corresponding to 3-8 PM). The circadian effects on the platelet activation markers were always larger than that of any of the three behavioral stressors. CONCLUSIONS/SIGNIFICANCE: These data demonstrate robust effects of the endogenous circadian system on platelet activation in humans--independent of the sleep/wake cycle, other behavioral influences and the environment. The 9 AM timing of the circadian peaks of the three platelet surface markers, including platelet surface activated GPIIb-IIIa, the final common pathway of platelet aggregation, suggests that endogenous circadian influences on platelet function could contribute to the morning peak in adverse cardiovascular events as seen in many epidemiological studies.
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There are effects of the circadian system on platelet activation, with a morning peak in platelet surface-activated GPIIb-IIIa, the final part of the platelet aggregation pathway.
“There are also effects of the circadian system on platelet activation, with a morning peak in platelet surface-activated GPIIb-IIIa, the final part of the platelet aggregation pathway (115).”
From Role of the circadian system in cardiovascular disease (2018) · cites this paper as [115]
Platelet count and aggregability peaked at a circadian phase equivalent to 3-8 PM.
“Platelet count and aggregability peaked at a circadian phase equivalent to 3–8 PM”
From The impact of the circadian timing system on cardiovascular and metabolic function (2012) · cites this paper as Scheer et al., 2011
Platelet size and surface expressions of activated GPIIb-IIIa, P-selectin, and GP1b were greatest during the biological morning, corresponding to 6 AM to noon.
“platelet size and surface expressions of activated GPIIb-IIIa, P-selectin, and GP1b were all greatest during the biological morning, corresponding to 6 AM to noon”
From The impact of the circadian timing system on cardiovascular and metabolic function (2012) · cites this paper as Scheer et al., 2011
The reactivity of platelet measures to mental, postural, and physical stress was not significantly influenced by the circadian timing system, and the influence of the circadian timing system and behavioral stressors appear additive.
“The reactivity of the above platelet measures to mental, postural, and physical stress was not significantly influenced by the circadian timing system, and thus, the influence of the circadian timing system and that of behavioral stressors appear to be additive”
From The impact of the circadian timing system on cardiovascular and metabolic function (2012) · cites this paper as Scheer et al., 2011
In healthy humans, platelet size, count, aggregability, and platelet surface expression of activated GPIIb-IIIa, P-selectin, and GP1b are influenced by the circadian timing system.
“Recent work has demonstrated in healthy humans that platelet size, count, aggregability, and platelet surface expression of activated GPIIb-IIIa, P-selectin, and GP1b—factors involved in the pathway of platelet aggregation and adhesion to subendothelial tissue (Merten et al., 2000; Phillips et al., 1988; Sadler, 1998)—are influenced by the circadian timing system”
From The impact of the circadian timing system on cardiovascular and metabolic function (2012) · cites this paper as Scheer et al., 2011
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- Authors
- Scheer, F. A. J. L., Michelson, A. D., Frelinger, A. L., Evoniuk, H., Kelly, E. E., McCarthy, M., Doamekpor, L. A., Barnard, M. R., & Shea, S. A.
- Affiliations
- Brigham and Women's Hospital (US)
- Boston Children's Hospital (US)
- Corresponding author
- Scheer, Frank A. J. L.
- Shea, Steven A.
- ORCID
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2011-09-08
- Volume
- 6
- Issue
- 9
- Pages
- e24549
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3169622
- OpenAlex
- W2049166597
- Cited by
- 206
- References
- 36
- Citations by year
- 2026: 11 · 2025: 14 · 2024: 16 · 2023: 18 · 2022: 19 · 2021: 16 · 2020: 14 · 2019: 16 · 2018: 16 · 2017: 13 · 2016: 8 · 2015: 18 · 2014: 14 · 2013: 7 · 2012: 5
- FWCI
- 3.84
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Brigham and Women's Hospital (M01 RR02635)
- Deutsches Krebsforschungszentrum
- National Institutes of Health (NIH-R01, NCRR-GCRC-M01-RR02635, RR‐02635)
- U.S. Public Health Service (NCRR-GCRC-M01-RR02635)
- National Heart, Lung, and Blood Institute (NIH-R01-HL76409, NIH-K24-HL076446, K24HL076446, NIH-P30-HL101299, R01HL076409, P30HL101299)
- National Center for Research Resources (RR02635, M01 RR 02635, GCRC-M01-RR02635, UL1RR025758, M01RR002635)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Health Sciences › Medicine › Hematology › Platelet Disorders and Treatments
- Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
- Keywords
- circadian rhythm, platelet activation, morning surge, platelet membrane glycoproteins, GPIIb/IIIa, P-selectin, platelet aggregation, mental arithmetic, physical activity, epinephrine, ATP release, cardiovascular events
- MeSH terms
- Adult, Behavior, Blood Pressure, Body Temperature, Cardiovascular System, Circadian Rhythm, Female, Humans, Light, Male, Stress, Psychological, Temperature, Time Factors, Exercise, Platelet Activation
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