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

Abstract

Objective-Diurnal variations in levels of factor VII (FVII), FVIII, proteins C and S, antithrombin, plasminogen activator inhibitor-1, prothrombin fragment F 1ϩ2 , 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 (ϩ11%) and in mice at the light-to-dark transition (ϩ63%), 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 humans and mice, temporal variations in TFPI activity. The coherent variations in FVII and TFPI activity could interplay to maintain the coagulation equilibrium. The chronobiological patterns should be considered to analyze activity levels of these factors. Moreover, the mouse model could be exploited to investigate modifiers of coagulation rhythms potentially associated to morning peaks of cardiovascular events. Key Words: factor VII Ⅲ TFPI Ⅲ circadian Ⅲ feeding schedule Ⅲ mouse model F requencies of thromboembolic events in humans exhibit marked diurnal variations, 1-3 with peaks from morning to noon. Temporal variations in the occurrence of hemorrhagic events have also been reported. 4 Fluctuations in coagulation factor levels able to influence the hemostatic balance might contribute to these adverse outcomes. Diurnal rhythms in levels of factor VII (FVII), 5 FVIII, 6 proteins C and S 7 , antithrombin, 7 and plasminogen activator inhibitor (PAI)-1 8 have been described in healthy humans. Temporal oscillations in prothrombin fragment F 1ϩ2 5-6 and D-dimer, 6 markers of thrombin generation and fibrinolysis, have been also described. These variations could reflect the existence of circadian rhythms of blood coagulation factors. Circadian rhythms are the overt expression of an internal timing mechanism measuring daily time, with the fundamental adaptive function of providing optimal temporal organization of physiological processes in relation to the environment. 9 Because formal assessment of circadian rhythms in coagulation factor levels is hardly feasible in humans, a circadian control has been so far demonstrated in a mouse model for PAI-1 10 -11 and fibrinogen 12 mRNA expression.Among factors interacting with circadian rhythms, daily availability of food represents a major component. Several studies suggested that postprandial and fasting lipoproteins are associated with plasma levels or activation state of coagulation factors, and particularly of FVII 13-17 that plays a key role in the initiation of the clott...

Salivary tissue factor induces thrombin generation in a diurnal rhythm

“…Moreover, various hemostatic factors are known to be subject to circadian variations. For instance, FVII and TF pathway inhibitor (TFPI) peak in the morning 21. Hence, evidence suggests the existence of a relatively procoagulant status in the morning, supported by a preponderance of thromboembolic events early on the day 22.…”

Chronic sleep deprivation markedly reduces coagulation factor VII expression

“…[18][19][20][21] Since sleep and wake cycles and the circadian system closely interact with each other, we investigated whether partial sleep deprivation has any effect on the thrombin generation activity in plasma, a parameter defining the coagulation cascade efficiency. 22 To this purpose, we exploited the mouse model and a recently developed PSD protocol.…”

“…A similar mechanism has been suggested by the parallel temporal oscillations in levels of FVII and of its direct inhibitor tissue factor pathway inhibitor. 19 Further studies aimed at evaluating the impact of sleep deprivation on plasma levels of a wide panel of coagulation and fibrinolytic factors are needed to address the physiopathology of this complex pathway.…”

Circadian rhythm and cardiovascular disorders

“…129,130 The hypercoagulability noted in the early morning is also associated with a peak in tissue factor pathway inhibitor and activated factor VII levels. 131,132 Further, the number of vascular cell adhesion molecule-1-positive microparticles released from the endothelium in human plasma was reported to show a peak at 9 am, and was associated with increased coagulability through the tissue factor pathway. 133 Further, levels of both prothrombin fragment (a marker for intravascular thrombin generation) and the plasmin-plasmin inhibitor complex (representing the degree of intravascular plasmin generation) were found to peak at 8 am.…”