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The Human Endogenous Circadian System Causes Greatest Platelet Activation during the Biological Morning Independent of Behaviors
Open accessAbstract
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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In the citing paper
“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]
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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 the citing paper
“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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Citations
Cites
Adverse metabolic and cardiovascular consequences of circadian misalignment
Scheer, F. A. J. L., Hilton, M. F., Mantzoros, C. S., & Shea, S. A. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0808180106 · Cited by 2,351
Self-citationResetting central and peripheral circadian oscillators in transgenic rats
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Circadian Variation in the Frequency of Onset of Acute Myocardial Infarction
Muller, J. E., Stone, P. H., Turi, Z. G., Rutherford, J. D., Czeisler, C. A., Parker, C., Poole, W. K., Passamani, E., Roberts, R., Robertson, T., et al. (1985) · New England Journal of Medicine · doi:10.1056/nejm198511213132103 · Cited by 1,884
Stability, precision, and near-24-hour period of the human circadian pacemaker
Czeisler, C. A., Duffy, J. F., Shanahan, T. L., Brown, E. N., Mitchell, J. F., Rimmer, D. W., Ronda, J. M., Silva, E. J., Allan, J. S., Emens, J. S., et al. (1999) · Science · doi:10.1126/science.284.5423.2177 · Cited by 1,705
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Changes in the platelet membrane glycoprotein IIb.IIIa complex during platelet activation.
Shattil, S. J., Hoxie, J. A., Cunningham, M. C., & Brass, L. F. (1985) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)39154-8 · Cited by 942
Circadian clocks in human red blood cells
O'Neill, J. S., & Reddy, A. B. (2011) · Nature · doi:10.1038/nature09702 · Cited by 843
Increased risk of ischaemic heart disease in shift workers
Knutsson, A., Jonsson, B., Akerstedt, T., & Orth-Gomer, K. (1986) · The Lancet · doi:10.1016/s0140-6736(86)91619-3 · Cited by 459
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Irregular sleep and all-cause mortality: A large prospective cohort study.
KADOTANI, H., 高嶋, 直., 門田, 文., Omichi, C., Koyama, T., Ozaki, E., Tomida, S., Yoshida, T., Otonari, J., Ikezaki, H., et al. (2022) · Institutional Repositories DataBase (IRDB)
Chen, Q., Chen, J., Chen, X., Yan, G., Niu, P., Shujuan, L., & Zhou, Y. (2026) · Frontiers in Neuroscience · doi:10.3389/fnins.2026.1942262
Chu, Z., Zhang, C., Lambert, L.-A., Ackermann, J., Brittberg, M., & Razak, H. R. B. A. (2026) · Cartilage · doi:10.1177/19476035261490284
Yang, M., Qian, X., Lin, W., & Yang, R. (2026) · Metabolites · doi:10.3390/metabo16110805
Shift Work and Acute Coronary Syndrome: Mechanisms, Modifying Factors, and Clinical Prevention
Wang, L., Ganesan, K., Liu, X., Yu, L., & Chen, Q. (2026) · Healthcare · doi:10.3390/healthcare14213651
Metadata
- 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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