Biological rhythms are a universal phenomenon in living organisms and serve to help organisms adapt within a circadian cycle to the 24-hour-oscillating environment. The rhythmic modulation of selective pathways thus enables organisms to optimize their ability to store and generate chemical energy, to minimize environmental stresses, and to reproduce by cycles of cell growth and division. Remarkably, the onset of both cardiovascular disorders and venous thromboembolism also undergoes circadian oscillations, which might be closely related to an internal biological clock. A highly repetitive rhythmic cycle seems to modulate platelet and endothelial functions, as well as the concentration and activity of several proteins of the coagulation and fibrinolytic systems. Although it is currently unknown how the global hemostatic efficiency might be affected by these circadian variations, understanding the nature, clinical significance, and pathophysiologic consequences of our hemostatic clock may be helpful for the prevention and treatment of a variety of conditions where either the severity of the illness or therapeutic efficacy exhibit circadian rhythmicity. In this review, clinical and laboratory data describing the effects of these cyclical rhythms on the hemostatic system are discussed.

Circadian variation within hemostasis: an underrecognized link between biology and disease?

Background
Cardiovascular diseases are frequent in patients with obstructive sleep apnea (OSAS). There is evidence that the day–night pattern of myocardial infarction and sudden cardiac death observed in the general population is altered in patients with OSAS. This study investigates potential abnormalities in the circadian profiles of platelet activity in OSAS.

Impaired circadian variation of platelet activity in patients with sleep apnea.

Hypofibrinolysis is a risk factor for venous and arterial thrombosis, and can be assessed by using a turbidimetric tPA-induced clot lysis time (CLT) assay. Biological variation in clot lysis time may affect the interpretation and usefulness of CLT as a risk factor for thrombosis. Sufficient information about assay variation and biological variation in CLT is not yet available. Thus, this study aimed to determine the analytical, within-subject and between-subject variation in CLT. We collected blood samples from 40 healthy individuals throughout a period of one year (average 11.8 visits) and determined the CLT of each plasma sample in duplicate. The mean (± SD) CLT was 83.8 (± 11.1) minutes. The coefficients of variation for total variation, analytical variation, within-subject variation and between-subject variation were 13.4%, 2.6%, 8.2% and 10.2%, respectively. One measurement can estimate the CLT that does not deviate more than 20% from its true value. The contribution of analytical variation to the within-subject variation was 5.0%, the index of individuality was 0.84 and the reference change value was 23.8%. The CLT was longer in the morning compared to the afternoon and was slightly longer in older individuals (> 40 years) compared to younger (≤40 years) individuals. There was no seasonal variation in CLT and no association with air pollution. CLT correlated weakly with fibrinogen, C-reactive protein, prothrombin time and thrombin generation. This study provides insight into the biological variation of CLT, which can be used in future studies testing CLT as a potential risk factor for thrombosis.

Biological variation in tPA-induced plasma clot lysis time.

The circadian clock, influencing many biological processes, has been demonstrated to modulate levels of specific coagulation factors, but its impact on the coagulation efficiency is unknown. In a mouse model, the authors evaluated the temporal variations in the initial rate of activated factor X (FXa) and thrombin generation. Upon coagulation activation through the FVIIa-TF pathway (extrinsic activation), both parameters showed rhythmic variations with a significant peak at ZT 12, the light-to-dark transition. In mice subjected to a 6-h delayed light-dark cycle, the peak was shifted as expected. These cyclic oscillations were also observed in constant darkness, thus demonstrating, for the first time, the existence of strong circadian rhythms of the initial rate of either FXa or thrombin generation activity levels. These circadian variations overlapped with those that have been recently described in factor VII (FVII) activity. The peak of FXa generation activity was simulated by the addition of purified human FVII, thus indicating that circadian variations in FVII activity are important determinants of the circadian rhythm of the procoagulant cascade efficiency. These findings help to elucidate the complex control on the coagulation process and might contribute in explaining the temporal variations in the frequency of cardiovascular events observed in humans.

Circadian rhythms in mouse blood coagulation.

While athletes are often considered the epitome of health due to their physique and lowered potential for metabolic and cardiovascular diseases, they may also be at risk for the onset and development of venous thromboembolism (VTE) In an attempt to achieve and remain competitive, athletes are frequently exposed to numerous athlete-specific risk factors, which may predispose them to VTE through the disruption of factors associated with Virchow's triad (ie, hypercoagulability, venous stasis, and vessel wall injury) Indeed, hypercoagulability within an athletic population has been well documented to occur due to a combination of multiple factors including exercise, dehydration, and polycythemia Furthermore, venous stasis within an athletic population may occur as a direct result of prolonged periods of immobilization experienced when undertaking long-distance travels for training and competition, recovery from injury, and overdevelopment of musculature While all components of Virchow's triad are disrupted, injury to the vessel wall has emerged as the most important factor contributing to thrombosis formation within an athletic population, due to its ability to influence multiple hemostatic mechanisms Vessel wall injury within an athletic population is often related to repetitive microtrauma to the venous and arterial walls as a direct result of sport-dependent trauma, in addition to high metabolic rates and repetitive blood monitoring Although disturbances to Virchow's triad may not be detrimental to most individuals, approximately 1 in 1,000 athletes will experience a potentially fatal post-exercise thrombotic incidence When acquired factors are considered in conjunction with genetic predispositions to hypercoagulability present in some athletes, an overall increased risk for VTE is present

Acquired and genetic thrombotic risk factors in the athlete

Objective— Diurnal variations in levels of factor VII (FVII), FVIII, proteins C and S, antithrombin, plasminogen activator inhibitor-1, prothrombin fragment F1+2, and D-dimers in healthy humans point to the existence of circadian rhythms of coagulation factors. We sought for temporal fluctuations of tissue factor pathway inhibitor (TFPI) activity in human and mouse plasma. Methods and Results— TFPI activity showed significant daily variations with highest levels in the morning in healthy men (+11%) and in mice at the light-to-dark transition (+63%), the beginning of the physically active period. Variations in FVII activity paralleled those in TFPI. In mice, the feeding schedule had a strong impact on these rhythms. Although restricted feeding and fasting shifted the peak of TFPI, the FVII peak disappeared. Investigation of temporal fluctuations in constant darkness indicated the existence of daily rhythms for TFPI and of true circadian rhythms for FVII. Conclusions— For the first time, we report, both in ...

Daily and Circadian Rhythms of Tissue Factor Pathway Inhibitor and Factor VII Activity

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Daily and Circadian Rhythms of Tissue Factor Pathway Inhibitor and Factor VII Activity