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Coated‐platelet levels are influenced by smoking, aspirin, and selective serotonin reuptake inhibitors

2007; Elsevier BV; Volume: 5; Issue: 10 Linguagem: Inglês

10.1111/j.1538-7836.2007.02691.x

1538-7933

Călin I. Prodan, Phillip Joseph, Andrea S. Vincent, George L. Dale,

Atrial Fibrillation Management and Outcomes

Coated-platelets are a subpopulation of platelets observed upon dual-agonist stimulation with collagen and thrombin [1]. Unlike single-agonist activated platelets, coated-platelets support a robust prothrombinase activity and express high levels of several procoagulant proteins on their surface including factor V, fibrinogen, fibronectin, thrombospondin and von Willebrand factor [1]. Procoagulant proteins on coated-platelets are conjugated with serotonin via a transglutaminase-mediated reaction, and fibrinogen and thrombospondin bound to the platelet surface provide binding sites to stabilize serotonin-conjugated proteins [1]. The ability to produce coated-platelets varies dramatically among normal blood donors, ranging from 15% to 55% [1], although the basis for this wide variability is unknown. Prompted by the procoagulant potential of coated-platelets [1] and our previous unpublished observations, we have examined the effect of cigarette smoking, HMG-CoA reductase inhibitors (statins), selective serotonin reuptake inhibitors (SSRI) and antiplatelet agents on coated-platelet production in adults. Seventy subjects from the University of Oklahoma Health Sciences Center and Oklahoma City Veterans Administration Medical Center were enrolled in the study. The study was approved by the Institutional Review Board, and informed consent was obtained for all study subjects. The study population consisted of hospital volunteers, visitors and employees. Exclusion criteria included: concurrent diagnosis of dementia, stroke, transient ischemic attack (TIA), acute coronary syndrome (ACS), active infectious disease, bleeding diathesis or previous history of stroke, TIA or ACS within one year of enrollment. Smoking status, medications, gender and age were recorded at the time of enrollment. All individuals on antiplatelet medication reported daily use of aspirin ranging between 81.5 and 325 mg. Race was recorded through self-identification for all study subjects. The subjects' mean age was 64.8 ± 8.15 years (mean ± SD). The clinical characteristics of this study population including demographics, smoking status and use of aspirin, SSRI and statin medications are listed in Table 1. Blood was drawn, platelet-rich plasma was prepared, and coated-platelets were assayed as described [1, 2]. Briefly, platelets were activated concurrently with thrombin and convulxin, a ligand for the collagen receptor glycoprotein VI, and the coated-platelet population was identified by its ability to bind biotinylated-fibrinogen [2]. Analysis was performed by flow cytometry, and coated-platelets were expressed as a percentage of all platelets [2]. Statistical analyses were performed using sas (SAS System for Windows, version 8.2, SAS Institute Inc., Cary, NC, USA). Multiple-way anovas were conducted to evaluate the effect of smoking, gender, race and use of aspirin, SSRIs and statins on coated-platelet synthesis. Regression analyses were used to evaluate relationships between coated-platelets levels and other independent variables (e.g. age). A P-value of < 0.05 was considered to be statistically significant. The subjects' coated-platelet levels were 31.6% ± 13.2% (mean ± SD), with a range from 6.7% to 58.9%, consistent with previous published findings [1]. A six-way anova was conducted to evaluate the effects of gender, race, smoking status, aspirin, statins and SSRIs on coated-platelets levels. All main effects and two-way interactions were considered. Non-significant interactions were excluded from the final model. Significant main effects were detected for smoking status [F(1, 62) = 6.3, P = 0.015], use of aspirin [F(1, 62) = 5.6, P = 0.022] and use of SSRIs [F(1, 62) = 4.2, P = 0.046]. Specifically, coated-platelet levels were significantly higher in individuals currently smoking when compared to individuals not smoking (32.6% ± 4.1%, n = 14 vs. 23.2% ± 3.1%, n = 56; adjusted mean ± 1SEM). Subjects taking aspirin had significantly lower coated-platelet levels than those not on aspirin (23.8% ± 4.0%, n = 22 vs. 32.0 ± 3.1, n = 48). Individuals using SSRIs had significantly lower coated-platelet levels when compared with persons not taking SSRIs (21.9% ± 5.6%, n = 5 vs. 33.9 ± 2.3, n = 65). The main effects for gender, race and statin use were not statistically significant for coated-platelet synthesis (P-values > 0.19). However, a significant interaction for coated-platelet potential was detected between race and statin use [F(1, 62) = 6.0, P = 0.018]. Specifically, coated-platelet levels were significantly higher in black subjects using statins than in black subjects not using statins (36.9% ± 4.2%, n = 12 vs. 23.2 ± 4.2%, n = 16; P = 0.03). In contrast, no statistically significant difference was detected in white subjects using statins compared to the white subjects not using statins (P = 0.68). Lastly, regression analyses performed to analyze a potential relationship between age and coated-platelet levels indicated the lack of any significant correlation between these measurements in our population (P = 0.99). These data confirm our anecdotal observations that current cigarette smokers have higher coated-platelet levels than non-smokers. This finding is particularly relevant as smoking has been identified as a major risk factor for cardiovascular disease [3]. The mechanism by which smoking affects coated-platelet potential is unclear, although animal studies have shown that inflammation can increase coated-platelet formation [1], and smoking is clearly pro-inflammatory [4]. Whether this is the primary explanation for the effect of smoking on coated-platelets will require additional investigation. The effect of aspirin on coated-platelet potential was unexpected. Our own observations indicated that intermittent aspirin use had little effect on coated-platelets (unpublished observation), but the data presented here clearly demonstrate that chronic aspirin use lowers coated-platelet potential. In vitro observations have shown that inhibition of prostacyclin synthesis by aspirin does affect megakaryocyte development [5], thereby laying a possible foundation for aspirin's ability to modify platelet characteristics, including the proportion of coated-platelets generated. Future studies examining the molecular mechanism of aspirin's effect on coated-platelet synthesis are warranted, considering the central role of antiplatelets in cardiovascular disease therapy. The decreased coated-platelet production in individuals taking SSRIs reached significance despite the small number of subjects currently on these medications. SSRIs are known to decrease dense granule serotonin in platelets as these cells have the same serotonin transport protein that is targeted in the central nervous system by this class of medications [6], and serotonin is critical to the production of coated-platelets [1]. Previous research has documented that individuals taking SSRIs have a mild bleeding tendency [7] and a decreased risk of a myocardial infarction, particularly among individuals who smoke [8]. No molecular explanation has been widely accepted for the protective effect of SSRI medications against myocardial infarction, but an impact on coated-platelet potential is a good candidate. We anticipated an effect of statins on coated-platelet formation because inflammation apparently potentiates coated-platelet production [1] and statins are known to attenuate inflammation [9]. While no significant main effect for statins was observed, a significant interaction between statins and race in coated-platelet production was noted. While racial/ethnic differences in medication effectiveness have been reported in the medical literature [10], no specific data have been published for statins. The current observation may indicate the existence of such a differential response in black individuals compared to white individuals with regards to statins. Given the fact that statins are reported to have a protective effect against stroke and ACS [11, 12] and that racial/ethnic differences have been consistently reported in cardiovascular diseases [13], the effect of statins on coated-platelet production deserves further exploration. In conclusion, our study indicates that smoking, aspirin and SSRIs significantly alter coated-platelet production in normal adults, whereas age and gender have no effect. Racial/ethnic differences complicate the effect of statins on coated-platelet levels, leading to a differential response in coated-platelet production between black individuals and white individuals. The wide range of coated-platelet levels noted here and elsewhere [1], together with the observation that coated-platelet levels are relatively stable in individual donors [1], strengthens the case for examining this subset of platelets in clinical prothrombotic settings. The authors state that they have no conflict of interest. This work was supported in part by the National Institutes of Health (HL68129) to G. L. Dale and a Veterans Affairs VISN 16 grant to C. I. Prodan. The authors are indebted to Bobbie Branscum-Parrish, RN, Rosetta Sledge, REEGT and Paul Friese, BS for their assistance with this project.