The Human Endogenous Circadian System Causes Greatest Platelet Activation During the Biological Morning Independent of Behaviors

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2011 Sep 21

PMID 21931750

Citations 77

Authors

Frank A J L Scheer

Alan D Michelson

Andrew L Frelinger 3rd

Heather Evoniuk

Erin E Kelly

Mary McCarthy

Lauren A Doamekpor

Marc R Barnard

Steven A Shea

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Thrombocytopenia in the intensive care unit: diagnosis and management.

Pene F, Russell L, Aubron C Ann Intensive Care. 2025; 15(1):25.

PMID: 39985745 PMC: 11846794. DOI: 10.1186/s13613-025-01447-x.

Sleep as a window of cardiometabolic health: The potential of digital sleep and circadian biomarkers.

van den Brink W, Oosterman J, Smid D, de Vries H, Atsma D, Overeem S Digit Health. 2025; 11:20552076241288724.

PMID: 39980570 PMC: 11840856. DOI: 10.1177/20552076241288724.

Complement Immune System in Pulmonary Hypertension-Cooperating Roles of Circadian Rhythmicity in Complement-Mediated Vascular Pathology.

DeVaughn H, Rich H, Shadid A, Vaidya P, Doursout M, Shivshankar P Int J Mol Sci. 2024; 25(23).

PMID: 39684535 PMC: 11641342. DOI: 10.3390/ijms252312823.

Longitudinal timing of physical activity and associated cardiometabolic and behavioral health outcomes in young adults.

Bailey C, Elmi A, Qian J, DiPietro L, Tackney M, Napolitano M Ann Behav Med. 2024; 59(1).

PMID: 39658316 PMC: 11783297. DOI: 10.1093/abm/kaae084.

Implementation of aspirin use during pregnancy in community midwifery-led care in the Netherlands: A pilot survey.

Bij de Weg J, van Doornik R, van den Auweele K, de Groot C, de Boer M, de Vries J Eur J Midwifery. 2024; 8.

PMID: 39091996 PMC: 11292730. DOI: 10.18332/ejm/191161.

References

Yamazaki S, Numano R, Abe M, Hida A, Takahashi R, Ueda M . Resetting central and peripheral circadian oscillators in transgenic rats. Science. 2000; 288(5466):682-5. DOI: 10.1126/science.288.5466.682. View

Andrews N, Gralnick H, Merryman P, VAIL M, Quyyumi A . Mechanisms underlying the morning increase in platelet aggregation: a flow cytometry study. J Am Coll Cardiol. 1996; 28(7):1789-95. DOI: 10.1016/S0735-1097(96)00398-1. View

Holme S, Heaton A, Konchuba A, Hartman P . Light scatter and total protein signal distribution of platelets by flow cytometry as parameters of size. J Lab Clin Med. 1988; 112(2):223-31. View

Casetta I, Granieri E, Fallica E, la Cecilia O, Paolino E, Manfredini R . Patient demographic and clinical features and circadian variation in onset of ischemic stroke. Arch Neurol. 2002; 59(1):48-53. DOI: 10.1001/archneur.59.1.48. View

Somanath P, Podrez E, Chen J, Ma Y, Marchant K, Antoch M . Deficiency in core circadian protein Bmal1 is associated with a prothrombotic and vascular phenotype. J Cell Physiol. 2010; 226(1):132-40. PMC: 2982145. DOI: 10.1002/jcp.22314. View

Ruggeri Z . Platelets in atherothrombosis. Nat Med. 2002; 8(11):1227-34. DOI: 10.1038/nm1102-1227. View

Scheer F, Czeisler C . Melatonin, sleep, and circadian rhythms. Sleep Med Rev. 2005; 9(1):5-9. DOI: 10.1016/j.smrv.2004.11.004. View

Coller B . Platelet GPIIb/IIIa antagonists: the first anti-integrin receptor therapeutics. J Clin Invest. 1997; 99(7):1467-71. PMC: 507964. DOI: 10.1172/JCI119307. View

Shattil S, Hoxie J, Cunningham M, Brass L . Changes in the platelet membrane glycoprotein IIb.IIIa complex during platelet activation. J Biol Chem. 1985; 260(20):11107-14. View

10.

LIBRE E, Cowan D, Watkins Jr S, Shulman N . Relationships between spleen, platelets and factor 8 levels. Blood. 1968; 31(3):358-68. View

11.

Kroll M, Harris T, Moake J, Handin R, Schafer A . von Willebrand factor binding to platelet GpIb initiates signals for platelet activation. J Clin Invest. 1991; 88(5):1568-73. PMC: 295673. DOI: 10.1172/JCI115468. View

12.

Ohkura N, Oishi K, Sudo T, Hayashi H, Shikata K, Ishida N . CLOCK regulates circadian platelet activity. Thromb Res. 2008; 123(3):523-7. DOI: 10.1016/j.thromres.2008.03.009. View

13.

Hu K, Scheer F, Laker M, Smales C, Shea S . Endogenous circadian rhythm in vasovagal response to head-up tilt. Circulation. 2011; 123(9):961-70. PMC: 3089897. DOI: 10.1161/CIRCULATIONAHA.110.943019. View

14.

Shea S, Hilton M, Hu K, Scheer F . Existence of an endogenous circadian blood pressure rhythm in humans that peaks in the evening. Circ Res. 2011; 108(8):980-4. PMC: 3086568. DOI: 10.1161/CIRCRESAHA.110.233668. View

15.

Zhao Y, Zhang Y, Wang S, Hua Z, Zhang J . The clock gene Per2 is required for normal platelet formation and function. Thromb Res. 2010; 127(2):122-30. DOI: 10.1016/j.thromres.2010.11.025. View

16.

Scheer F, Hu K, Evoniuk H, Kelly E, Malhotra A, Hilton M . Impact of the human circadian system, exercise, and their interaction on cardiovascular function. Proc Natl Acad Sci U S A. 2010; 107(47):20541-6. PMC: 2996667. DOI: 10.1073/pnas.1006749107. View

17.

Roden M, Koller M, Pirich K, Vierhapper H, Waldhauser F . The circadian melatonin and cortisol secretion pattern in permanent night shift workers. Am J Physiol. 1993; 265(1 Pt 2):R261-7. DOI: 10.1152/ajpregu.1993.265.1.R261. View

18.

Knutsson A, Akerstedt T, Jonsson B, Orth-Gomer K . Increased risk of ischaemic heart disease in shift workers. Lancet. 1986; 2(8498):89-92. DOI: 10.1016/s0140-6736(86)91619-3. View

19.

Cornelissen G, Halberg F, Prikryl P, Dankova E, Siegelova J, Dusek J . Prophylactic aspirin treatment: the merits of timing. International Womb-to-Tomb Chronome Study Group. JAMA. 1991; 266(22):3128-9. View

20.

Sack R, Blood M, Lewy A . Melatonin rhythms in night shift workers. Sleep. 1992; 15(5):434-41. DOI: 10.1093/sleep/15.5.434. View