Sleep-disordered Breathing and Prothrombotic Biomarkers: Cross-sectional Results of the Cleveland Family Study

Rationale: Individuals with sleep-disordered breathing (SDB) are at increased cardiovascular risk, possibly due to SDB-related stresses contributing to atherosclerosis.

Objectives: We postulate that pathways associated with a prothrombotic potential are up-regulated in SDB.

Methods: Morning and evening plasminogen activator inhibitor-1 (PAI-1), morning fibrinogen, and morning D-dimer were measured in 537 Cleveland Family Study adults. Piecewise multivariable linear mixed models estimated relative mean change or mean change in the biomarker per 5-unit increase in apnea-hypopnea index (AHI) in two groups: AHI less than 15 and AHI greater than or equal to 15, and hypoxia defined as percentage of sleep time with Sa(O(2)) less than 90% (< 2%, ≥ 2%).

Measurements And Main Results: Nonlinear associations were demonstrated: morning and evening PAI-1 increased by 12% (95% confidence interval [CI], 5-20%; P < 0.001) and 11% (95% CI, 2-20%; P = 0.01), respectively per 5-unit AHI increase until an AHI of 15, when no further increase in PAI-1 was demonstrated. The association between AHI and morning PAI-1 remained significant after adjusting for evening PAI-1 level (10%; 95% CI, 3-17%; P < 0.01). Morning fibrinogen increased on average by 8.4 mg/dl (95% CI, 3.12-13.65; P = 0.002) per five-unit AHI increase until an AHI of 15. There was no association between AHI and morning D-dimer. Hypoxia severity was not associated with thrombotic marker levels.

Conclusions: PAI-1 and fibrinogen levels increase monotonically with AHI at degrees of SDB considered mildly to moderately abnormal, suggesting that even mild SDB levels may increase prothrombotic processes. There may be a plateau in this effect, occurring at levels considered to reflect only moderate SDB severity. These relationships with mild-to-moderate SDB were not observed with D-dimer.