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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:646.)
© 2005 American Heart Association, Inc.

Thrombosis

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

Mirko Pinotti; Cristiano Bertolucci; Francesco Portaluppi; Ilaria Colognesi; Elena Frigato; Augusto Foà; Francesco Bernardi

From the Deparments of Biochimica e Biologia Molecolare (M.P., F.B.), Biologia and Centro di Neuroscienze (C.B., I.C., E.F., A.F.), and Medicina Clinica e Sperimentale (F.P.), Università degli Studi di Ferrara, Ferrara, Italy.

Correspondence to Mirko Pinotti, PhD, Dipartimento di Biochimica e Biologia Molecolare, Università di Ferrara, Via L. Borsari 46, 44100 Ferrara, Italia. E-mail pnm{at}unife.it

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 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.

In healthy humans, tissue factor pathway inhibitor (TFPI) and factor VII (FVII) activity levels showed significant diurnal variations. Parallel daily fluctuations in TFPI and FVII activity, influenced by the feeding schedule, were shown in mice. Only FVII rhythms were circadian. These chronobiological patterns should be considered to analyze activity levels of these factors.

Key Words: factor VII • TFPI • circadian • feeding schedule • mouse model

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