Increased platelet activation in sleep apnea subjects with intermittent hypoxemia

Abstract

Purpose: Obstructive sleep apnea (OSA) is independently associated with increased risk for stroke and other cardiovascular diseases. Since activated platelets play an important role in cardiovascular disease, the objective of this study was to determine whether platelet reactivity was altered in OSA subjects with intermittent nocturnal hypoxemia.

Methods: Thirty-one subjects, without hypertension or cardiovascular disease and not taking medication, participated in the study. Subjects were stratified based on OSA-related oxygen desaturation index (ODI) recorded during overnight polysomnography. Platelet reactivity to a broad panel of agonists (collagen, thrombin, protease-activated receptor1 hexapeptide, epinephrine, ADP) was measured by monitoring platelet aggregation and ATP secretion. Expression of platelet activation markers CD154 (CD40L) and CD62P (P-selectin) and platelet-monocyte aggregates (PMA) was quantified by flow cytometry.

Results: Epinephrine-induced platelet aggregation was substantially decreased in OSA subjects with significant intermittent hypoxemia (ODI ≥ 15) compared with subjects with milder hypoxemia levels (ODI < 15) (area under curve, p = 0.01). In addition, OSA subjects with ODI ≥ 15 exhibited decreased thrombin-induced platelet aggregation (p = 0.02) and CD40L platelet surface expression (p = 0.05). Platelet responses to the other agonists, CD62P platelet surface expression, and PMA levels were not significantly different between groups. Reduction in platelet responses to epinephrine and thrombin, and decreased CD40L surface marker expression in significant hypoxemic OSA individuals, is consistent with their platelets being in an activated state.

Conclusions: Increased platelet activation was present in otherwise healthy subjects with intermittent nocturnal hypoxemia due to underlying OSA. This prothrombotic milieu in the vasculature is likely a key contributing factor toward development of thrombosis and cardiovascular disease.

Trial registration: NCT00859950.

Keywords: Cardiovascular disease; Intermittent hypoxemia; Obstructive sleep apnea; Platelet activation; Platelet aggregation; Stroke.

Fig. 1. Epinephrine-induced platelet aggregation in subjects with significant intermittent hypoxemia as compared to subjects with milder hypoxemia levels.

Platelet aggregation in subjects with an ODI ≥ 15 as compared to subjects with an ODI < 15 in response to the agonist epinephrine (5μM). (a) The area under the curve (AUC) of agonist-induced platelet aggregation; (b) the amplitude of the aggregation response; and (c) the rate of platelet aggregation. Data are presented as median with box indicating upper and lower quartiles, whiskers indicating extrema, and with p values calculated by the non-parametric Wilcoxon rank-sum test (Mann-Whitney U test).

Fig. 2. Thrombin-induced platelet aggregation in subjects with significant intermittent hypoxemia as compared to subjects with milder hypoxemia levels.

Platelet aggregation in subjects with an ODI ≥ 15 as compared to subjects with an ODI < 15 in response to the agonist thrombin (1U/ml). (a) The area under the curve (AUC) of agonist-induced platelet aggregation and (b) the amplitude of the aggregation response. Data are presented as median with box indicating upper and lower quartiles, whiskers indicating extrema, and with p values calculated by the non-parametric Wilcoxon rank-sum test (Mann-Whitney U test).