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Diurnal rhythms in certain hemostatic factors may contribute to the clustering of various cardiovascular events at certain times of the day. We have been unable to find any diurnal variation in the hypercoagulable state associated with atrial fibrillation (AF), as indicated by variations in levels of von Willebrand factor, fibrinogen, soluble P-selectin and thrombomodulin, in patients with chronic AF, that could contribute to the high risk of stroke and thromboembolism associated with this arrhythmia (1). We are grateful to Peverill and Smolich for bringing to our attention a number of previous publications that they consider as having a bearing on the interpretation of our data.
Peverill and Smolich cite the study by Porta et al. (2), who reported differences in levels of von Willebrand factor (defined by immunoelectrophoresis) taken at 13 time points in nine patients with diabetes who were treated with insulin twice in a 12-h period. These data were analyzed by paired ttesting: we used the considerably more stringent Freidman’s repeated-measures two-way analysis of variance. Furthermore, von Willebrand factor levels are positively associated with insulin (3,4); consequently, we did not consider the data from Porta et al. (2)to be entirely comparable with ours. Peverill and Smolich also cite the reports by Kanabrocki et al. (5,6), which reported levels of fibrinogen taken at eight time points in 11 men (mean age 55 years) who were heterogeneous for cardiovascular disease (and its risk factors), and analyzed these data with a complex procedure (that is unavailable to us) involving “the fit of a cosine curve by the method of least squares.” Therefore, these subjects differ from those in our study of carefully selected patients with chronic AF.
Peverill and Smolich cite two papers reporting essential physiological changes in a cohort of healthy young men, a group most different to our patients with AF. For example, Jilma et al. (7)obtained five blood samples from 12 men (mean age 25 years) and found a diurnal variation in levels of soluble P-selectin. Similarly, Kirk et al. (8)took seven blood samples from nine men (mean age 23 years) and also found a variation in levels of soluble P-selectin. We were aware of both these papers during our study, but we failed to refer to them as they represent different patient populations to our own. However, we agree that, as we did not present data on the diurnal variation in soluble P-selectin and soluble thrombomodulin in healthy subjects, we were perhaps premature to interpret this data in terms of “loss” of a pattern in the patients with AF, although this lack of diurnal variation is in keeping with our hypothesis of a “constant” hypercoagulable state in AF.
Naturally, there are many confounders to be addressed in studies of thrombosis and hemostasis, and ours is typical in that atherosclerosis and its risk factors were present in some of our patients with AF. It has previously been shown that the hypercoagulable state in AF is independent of underlying etiology or associated heart disease (9), and we would emphasize that the main objective of our study was to assess the circadian or diurnal variation in the hypercoagulable state in AF, rather than to reproduce many previous analyses (including our own) of the effects of heart disease on hypercoagulability in AF. Indeed, we were unable to find any difference in our research indices comparing those patients with lone AF with those whose AF was confounded by other disease (1). Despite this, our cohort of patients are indeed characteristic of those presenting to the hospital with AF, and so the data are truly representative of a “real-life” situation.
- American College of Cardiology
- Li-Saw-Hee F.L.,
- Blann A.D.,
- Lip G.Y.H.
- Kanabrocki E.L.,
- Sothern R.B.,
- Messmore H.L.,
- et al.