vWF/ADAMTS13 is associated with on-aspirin residual platelet reactivity and clinical outcome in patients with stable coronary artery disease

Ellen M K Warlo, Alf-Åge R Pettersen, Harald Arnesen, Ingebjørg Seljeflot, Ellen M K Warlo, Alf-Åge R Pettersen, Harald Arnesen, Ingebjørg Seljeflot

Abstract

Background: 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.Our aim was to investigate whether ADAMTS13 and vWF/ADAMTS13 ratio were associated with high RPR, and further with clinical endpoints after 2 years.

Methods: Stable 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.

Results: The 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).

Conclusion: These 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 registration: Clinicaltrials.gov NCT00222261. Registered 13.09.2005. Retrospectively registered.

Keywords: ADAMTS13; Aspirin; Cardiovascular disease; Residual platelet reactivity; Von Willebrand factor.

Conflict of interest statement

Ethics approval and consent to participate

The ASCET study was approved by the Regional Committee for Medical Research Ethics, Health East with the ID-number: 652, conducted in accordance with the ethical principles of the Declaration of Helsinki. All patients gave their written informed consent to participate.

Consent for publication

Not applicable

Competing interests

The authors declare that they have no competing interest.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
a Endpoints during 2 years follow-up according to quartiles of vWF. p-value refers to trend analysis. b Endpoints during 2 years follow-up according to quartiles of vWF/ADAMTS13 antigen ratio. p-value refers to trend analysis

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