Abstract
BackgroundThe mechanisms behind residual platelet reactivity (RPR) despite aspirin treatment are not established. It has been shown that coronary artery disease (CAD) patients with high on-aspirin RPR have elevated levels of von Willebrand factor (vWF). ADAMTS13 is a metalloprotease cleaving ultra large vWF multimers into less active fragments.Our aim was to investigate whether ADAMTS13 and vWF/ADAMTS13 ratio were associated with high RPR, and further with clinical endpoints after 2 years.MethodsStable aspirin-treated CAD patients (n = 999) from the ASCET trial. RPR was assessed by PFA-100. ADAMTS13 antigen and activity were analysed using chromogenic assays. Endpoints were a composite of acute myocardial infarction, stroke and death.ResultsThe number of patients with high RPR was 258 (25.8%). Their serum thromboxane B2 (TxB2) levels were low, indicating inhibition of COX-1. They had significantly lower levels of ADAMTS13 antigen compared to patients with low RPR (517 vs 544 ng/mL, p = 0.001) and significantly lower ADAMTS13 activity (0.99 vs 1.04 IU/mL, p = 0.020). The differences were more pronounced when relating RPR to ratios of vWF/ADAMTS13 antigen and vWF/ADAMTS13 activity (p < 0.001, both). We found an inverse correlation between vWF and ADAMTS13 antigen (r = −0.14, p < 0.001) and ADAMTS13 activity (r = −0.11, p < 0.001). No correlations between TxB2 and ADAMTS13 antigen or activity, were observed, implying that ADAMTS13 is not involved in TxB2 production. Patients who experienced endpoints (n = 73) had higher vWF level (113 vs 105%, p = 0.032) and vWF/ADAMTS13 antigen ratio (0.23 vs 0.20, p = 0.012) compared to patients without. When dichotomizing vWF/ADAMTS13 antigen at median level we observed that patients above median had higher risk for suffering endpoints, with an adjusted OR of 1.86 (95% CI 1.45, 2.82).ConclusionThese results indicate that ADAMTS13 is of importance for RPR, and that it in combination with vWF also is associated with clinical endpoints in stable CAD patients on aspirin.Trial registrationClinicaltrials.gov NCT00222261. Registered 13.09.2005. Retrospectively registered.
Highlights
The mechanisms behind residual platelet reactivity (RPR) despite aspirin treatment are not established
It is involved in haemostasis when released as ultra-large multimers, and the activity decreases as the size abates [5]. von Willebrand factor (vWF)’s activity is enhanced by shear stress, promoting conformational changes of the molecule to expose important binding sites [6]. vWF is cleaved into smaller fragments with reduced thrombotic activity by a metalloproteinase, ADAMTS13, “A Disintegrin And Metalloprotease with TromboSpondin type 1 motif, member 13” [7]
The aim of the present study was to investigate whether ADAMTS13 alone and as a vWF/ADAMTS13 ratio were associated with the presence of high RPR in aspirin treated coronary artery disease (CAD) patients
Summary
The mechanisms behind residual platelet reactivity (RPR) despite aspirin treatment are not established. It has been shown that coronary artery disease (CAD) patients with high on-aspirin RPR have elevated levels of von Willebrand factor (vWF). ADAMTS13 is a metalloprotease cleaving ultra large vWF multimers into less active fragments. Von Willebrand factor (vWF) is an established marker of endothelial activation, and patients with elevated plasma levels of the ultra large vWF molecules are at high risk for future cardiovascular events [1,2,3,4]. VWF occurs in different lengths in the circulation and its thrombotic properties differ depending on its size [6] It is involved in haemostasis when released as ultra-large multimers, and the activity decreases as the size abates [5]. The importance of ADAMTS13 for platelet reactivity, indirectly by acting on vWF or directly, is limited described
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