Differences in Whole Blood Platelet Aggregation at Baseline and in Response to Aspirin and Aspirin Plus Clopidogrel in Patients With Versus Without Chronic Kidney Disease

Abstract

Thrombotic events while receiving antiplatelet agents (APAs) are more common in subjects with versus without chronic kidney disease (CKD). Data on antiplatelet effects of APA in CKD are scarce and limited by lack of baseline platelet function before APA treatment. We hypothesized subjects with stages 4 to 5 CKD versus no CKD have greater baseline platelet aggregability and respond poorly to aspirin and clopidogrel. In a prospective controlled study, we measured whole blood platelet aggregation (WBPA) in 28 CKD and 16 non-CKD asymptomatic stable outpatients not on APA, frequency-matched for age, gender, obesity, and diabetes mellitus. WBPA was remeasured after 2 weeks of each aspirin and aspirin plus clopidogrel. The primary outcome was percent inhibition of platelet aggregation (IPA) from baseline. The secondary outcome was residual platelet aggregability (RPA; proportion with <50% IPA). Baseline platelet aggregability was similar between groups except adenosine diphosphate-induced WBPA, which was higher in CKD versus non-CKD; median (interquartile range) = 13.5 (9.5 to 16.0) versus 9.0 (6.0 to 12.0) Ω, p = 0.007. CKD versus non-CKD participants had lower clopidogrel-induced IPA, 38% versus 72%, p = 0.04. A greater proportion of CKD versus non-CKD participants had RPA after clopidogrel treatment (56% vs 8.3%, p = 0.01). There were no significant interactions between CKD and the presence of cytochrome P450 2C19 polymorphisms for platelet aggregability in clopidogrel-treated participants. In conclusion, CKD versus non-CKD subjects exhibited similar platelet aggregation at baseline, similar aspirin effects and greater RPA on clopidogrel, which was independent of cytochrome P450 2C19 polymorphisms.

Trial registration: ClinicalTrials.gov NCT01768637.

Figure 1

Exclusionary cascade for derivation of sample. CKD, Chronic Kidney Disease.

Figure 2

A. Whole blood platelet aggregation (WBPA) induced by various agonists at baseline in chronic kidney disease (CKD) participants (closed bars) vs. non-CKD controls (open bars), expressed in ohms: 10 μM adenosine diphosphate (ADP10), 20 μM adenosine diphosphate (ADP20), 2 μg/mL collagen (collA2), 0.25 mM arachidonic acid (AAA0.25), 0.5 mM arachidonic acid (AAA00.5) and 1 mg/mL ristocetin (R_1mg_mL). B. Adenosine triphosphate (ATP) secretion response to various agonists at baseline in the CKD vs. non-CKD groups, expressed in nanomoles (nmoles): ATP secretion to 0.25 mM arachidonic acid (AAS0_25), to 0.5 mM arachidonic acid (AAS0_5), to 2 μg/mL collagen (CollS2), and to 1 unit/mL thrombin (ThrombinS). Results are presented as means ±standard deviation. Between-group significant differences are shown with asterisk (CKD vs. non-CKD), p=0.02 for ADP10 and p=0.007 for ADP20.

Figure 3

Aspirin effect in the chronic kidney disease (CKD) and the non-CKD groups as measured by the change in whole blood platelet aggregation (WBPA) induced by A) 0.5 mM arachidonic acid (AAA0.5) and B) 2 μg/mL collagen (CollA2) after 2 weeks of 81 mg of aspirin daily. Results are presented as mean and standard deviation. CKD is represented with closed circles and non-CKD with open triangles. There was a significant decrease in WBPA in both groups with CollA2 (p <0.0001) and with AAA0.5 (p <0.0001). The response at 2 weeks was not statistically different between CKD and non-CKD groups: group x time interaction p =0.29 for CollA2 and p =0.78 for AAA0.5.

Figure 4

Clopidogrel effect in the chronic kidney disease (CKD) (closed circles) vs. the non-CKD (open triangles) groups in whole blood platelet aggregation (WBPA) induced by A. 10 μM adenosine diphosphate (ADP10) and B. 20 μM adenosine diphosphate (ADP20) on 2 weeks of 81 mg of aspirin and 75 mg of clopidogrel daily. Results are presented as means ± standard deviation. Asterisk (*) shows that at Week 4 vs. Week 2, there was a significant decrease in WBPA in both groups induced by 10 μM ADP (p<0.0001) and 20 μM ADP (p<0.0001). The responses over time, i.e. at 2 weeks (aspirin 81 mg) and 4 weeks (aspirin 81 mg + clopidogrel 75 mg) of treatment, were not statistically different between CKD and non-CKD groups.

Figure 5

Clopidogrel effect in the chronic kidney disease (CKD) (right-side) vs. the non-CKD (left-side) groups in whole blood platelet aggregation (WBPA) induced by 20 μM adenosine diphosphate (ADP 20) based on metabolic phenotypes of CYP2C19 polymorphisms.