The value of aggregometry with arachidonic acid was very similar for the volunteers and the patients during aspirin intake and without aspirin and significantly lower at day 4 after aspirin cessation in the patients (Fig. 1). The values at day 3 were not significantly different (P = 0.126) owing to the wide variability in both the volunteer and patient groups.
In response to ADP, platelet aggregation decreased somewhat, although it remained far above the lower limit of normal (Table 5).
In an attempt to isolate the effect of aspirin from other medications being taken by the patient group (Table 6), we stratified the PAG results by the specific comorbidities and by the different medications. There were no differences in platelet aggregation in response to arachidonic acid or EPI between patients with or without ischaemic heart disease, noninsulin-dependent diabetes mellitus, hypertension, hyperlipidaemia, or chronic renal failure. Furthermore, there was no noticeable interaction between any of the medications being taken at the time of the study (nitrates, β-blockers, calcium-channel blockers, statins, antiglycaemic drugs, diuretics) and PAG. The only exception was angiotensin converting enzyme (ACE) inhibitor: values for PAG with EPI were lower during aspirin therapy in patients who were taking ACE inhibitors than in patients who were not (44.4 ± 11.8 vs. 55.4 ± 15.3%, P = 0.005). This difference, however, disappeared at 10 days after aspirin cessation (81.2 ± 21.6 vs. 87.1 ± 10.8%, P = 0.7). No such difference was noted for PAG with arachidonic acid between patients taking ACE inhibitors or not, either during aspirin therapy (16.5 ± 8.5 vs. 15.6 ± 7.2%, P = 0.21) or after aspirin cessation (90.2 ± 9.3 vs. 89.7 ± 4.4%, P = 0.8).
Additionally, comparison of the patients by interim day on which PAG was performed (3, 4 or 6 after aspirin cessation) revealed no differences in demographic data, preoperative haematological results, comorbidities or other medications used (Table 6).
The urine level of 11dhTx B2 in the patients was 1669 ± 965 pg ml−1 during aspirin treatment and rose to 5927 ± 5991 pg ml−1 after cessation of aspirin (P < 0.05; Table 4). This finding was highly significant despite the fact that two patients had opposite results: a higher thromboxane level during treatment with a full dose of aspirin than without aspirin. Both patients showed the expected PAG pattern of low aggregation during aspirin therapy and normal aggregation without aspirin.
There was no correlation of the changes in urine 11dhTx B2 level with platelet aggregation in either the volunteer or the patient group, and no correlation of thromboxane level with any of the patients' comorbidities or medications.
Of the total of seven patients who exhibited a slow return to normal levels of platelet aggregation, six were tested on interim day 3 and one was tested on interim day 4 (Fig. 2); all had similar 11dhTx B2 levels to those in rest of the patients.
The present study shows that, following the cessation of regular intake of aspirin, platelet function, measured in vitro, usually returns to normal within 3 days in healthy individuals and within 4 days in patients. Platelet recovery in some patients, however, can be delayed. These results, first, do not support the widespread practice of discontinuing regular aspirin intake 7–10 days before elective surgery9–15 and, second, demonstrate the difference in platelet recovery between volunteers and patients.
We used a prospective, longitudinal, two-phase study design. Measurements were performed with aggregometry, the most commonly used method for the quantitative assessment of platelet function in vitro.14 Different agonists were used (arachidonic acid, EPI, ADP) in order to evaluate different pathways of platelet activation. Arachidonic acid is specific to aspirin because it serves as a substrate for platelet cyclooxygenase (COX). Aspirin inhibits COX, thereby preventing discharge of the potent pro-aggregant substance, thromboxane A2, from platelets while, in low doses, sparing the synthesis of prostacyclin. By contrast, the platelet receptor for EPI is complex and affected by different substances by different mechanisms in different directions.20 The difference between the receptors may explain the more significant effect of aspirin on platelet aggregation in response to arachidonic acid than to EPI in the present study (Table 3). Alberts et al.21 reported that, in patients treated with aspirin for stroke, platelet aggregation in response to EPI remained normal. In our study, aggregation with ADP was not significantly affected by aspirin, whereas Ferrell et al.22 noted a distortion of the second phase of aggregation when ADP was used as the agonist.
We assessed aspirin at a dose of 100 mg per day for several reasons: it was the dose most frequently used in our patients; it is not sufficient to cause gastrointestinal complications such as bleeding;23 it is sufficient to neutralize more than 90% of thromboxane formation by platelets;22 its effect on platelet function is no different from the effect of aspirin at lower (75 mg) or higher (up to 300 mg) doses;15 this effect on platelet function is significantly more prominent than the effect of aspirin at a dose of 40 mg;24 and low doses of aspirin, as mentioned, preferentially inhibit platelet thromboxane A2 synthesis but not the production of antithrombotic prostacyclin by endothelial cells.1,2,5
Sonksen et al.,15 in a study of volunteers, reported that, after cessation of aspirin treatment, bleeding time recovered already after 48–72 h. Moreover, in a later study, Coleman and Alberts16 observed that, in healthy volunteers, a significant amount of platelet function recovers already 3 days after aspirin cessation and activity returns to normal after 5 days using a point-of-care assay device but not standard PAG.
The recommendation to wait 7–10 days until platelet function recovers is based on the assumption that aspirin inhibition of platelet COX is irreversible and neutralizes platelets for their whole lifespan.5 However, in the present study, according to the aggregometry measurements with both agonists, platelet function recovered earlier: after 3 days in volunteers and after 4 days in most patients. To explain this finding, we suggest that the effect of aspirin on megakaryocytes in bone marrow is not permanent, in contrast to platelets that are permanently impaired by the action of aspirin and are later removed from the circulation. The megakaryocytes in affected bone marrow can regenerate COX within 12 h after cessation of aspirin, constantly regenerating about 35 × 109 l−1 new normal platelets that are added to the circulation daily.25 In this manner, up to 15% of aspirin-affected platelets are replaced daily by intact platelets. If the platelets are not re-exposed to aspirin, the generation of new platelets leads to the gradual recuperation of overall platelet function.
The difference in recovery between the volunteers and patients might be explained by age (the volunteers were generally younger with more rapid metabolic and regeneration processes), general health status (the patients were sicker), and medications (taken only by the patients on a regular basis).
Various medications are known to affect platelet function. ACE inhibitors were found to lower levels of plasminogen activator inhibitor type 1 and decrease platelet aggregability26 and to inhibit platelet activation in congestive heart failure.27 Others noted that ACE inhibitors augment ecto-ATP diphosphohydrolase activity and enhance endothelial antiplatelet function in human umbilical vein endothelial cells,28 thereby impairing platelet aggregation, which could possibly augment the effect of aspirin. The effects of statins on platelet function and their interaction with aspirin are still controversial.29–32 According to our data, statin intake did not significantly alter the effect of aspirin on platelet function or the recovery of platelet function after aspirin cessation.
Comorbidities, too, may influence platelet function. Hypertension has a prothrombotic effect associated with a decrease in fibrinolytic activity, which is expressed as an increase in levels of plasma plasminogen activator inhibitor type 1 and greater platelet aggregability.26 Also, in diabetic patients, high glucose levels enhance platelet activation and aggregation and are associated with poor platelet responsiveness to aspirin in vitro.33–35
Faraday et al.36 reported that the phenotypic variability in platelet response to aspirin is genetically determined, though the specific genes involved are not known. Apparently, the relationship between genotype, aspirin-response phenotype, and clinical consequences is very complicated. We suggest that, in addition to clinical factors such as age, comorbidities, and medications, the slower recovery of platelet aggregation in some of the patients in our study (Fig. 2), compared with the volunteers and to other patients, might be attributable to individual genotype.
Our study has several limitations. First, we recruited only male volunteers in order to avoid the influence of female cyclic hormonal changes on the coagulation system in general and on platelets in particular.37–40 Second, we could not apply exactly the same protocol in the patients as we used in the volunteers, because we thought it unethical to draw blood from the patients on a daily basis. Third, we did not evaluate the clinical consequences of aspirin cessation, such as bleeding or cardiovascular events. We are aware, however, that patients treated preoperatively with aspirin have an increased tendency to bleeding after cardiac surgery and a lower incidence of postoperative myocardial infarction.41,42 Fourth, our sample size is limited and could not provide sufficient data for constructing a demographic and comorbidity model of platelet function recovery after aspirin.
Despite these drawbacks, we think that this study has proven that the aspirin effect on the platelet function vanished in the majority of patients in 4 days and in all patients 6 days after cessation of its intake. However, a minority of the patients showed a slower process of platelet recovery from aspirin influence up to the sixth day of aspirin cessation. This knowledge, on one hand, could be important for patients undergoing surgical procedures when serious perioperative bleeding could put a patient at risk. On the other hand, the precise timing of aspirin cessation is important because of the possible detrimental effect of interruption of aspirin therapy that can lead to ischaemic cerebral events.18,42 Mangano19 showed that early postoperative reinstitution of aspirin decreases cardiovascular complications. The duration of interruption of aspirin and other antiplatelet therapy before surgery could be life-threatening or life-saving, particularly in patients after angioplasty with different intracoronary stents.18 The main conclusion of this review18 was that the cessation of any antiplatelet therapy in patients with coronary stents should be as short as possible, if at all, to prevent stent thrombosis.
In conclusion, the present study shows that, in the majority of the patients treated with aspirin, platelet function recovers in 4 days after aspirin cessation compared with 3 days in healthy volunteers. Despite the fact that platelet function recovers after 4 days in the majority of patients, some patients might nevertheless have delayed recovery. We, therefore, suggest that the duration of aspirin cessation before elective surgical procedures with a high risk of potential bleeding should be 6 days, and that platelets should be monitored by aggregometry if this is not feasible.
We acknowledge Dr Ada Tamir for the statistical analysis; Drs Miriam David and Alisa Kessel, Lady Davis Carmel Medical Center, for their laboratory assistance; Dr Simon Gelman, Chairman Emeritus, Harvard University, Boston, Massachusetts, for the creative assistance during study design and preparation of the article.
The present study was partly supported by a grant from the Dankner Family Foundation, 2006.
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Keywords:© 2010 European Society of Anaesthesiology
aspirin; platelet aggregometry; platelets; thromboxane