Advances in Therapy

, Volume 36, Issue 9, pp 2296–2309 | Cite as

Association Between Residual Platelet Reactivity on Clopidogrel Treatment and Severity of Coronary Atherosclerosis: Intrinsic Hypercoagulability as a Mediator

  • Xin Zhao
  • Hongyi Wu
  • Huajie Xu
  • Li Shen
  • Bing FanEmail author
  • Junbo GeEmail author
Original Research



High on-treatment residual platelet reactivity (HRPR) was associated with greater atherosclerosis burden. We examined whether intrinsic hypercoagulability (IHC) could be attributed to that association in patients treated by drug-eluting stents.


This retrospective observation enrolled a total of 891 coronary artery disease (CAD) subjects. Platelet and coagulant reactivity was measured by thrombelastography. At least 24 h after a 300-mg dose of clopidogrel, adenosine diphosphate (ADP)-induced maximum amplitude of clot strength (MAadp) > 47 mm represented HRPR. Thrombin-induced platelet–fibrin clot strength (MAthrombin) and blood fibrinogen surrogated intrinsic coagulability. Using mediation analysis to evaluate the effect of IHC on the relationship between the number of narrowed coronaries and HRPR on clopidogrel.


More HRPR on clopidogrel and higher intrinsic coagulability were observed in more severe coronary atherosclerosis, especially in the three-vessel disease. After adjustment for confounding factors, the number of narrowed coronaries (ORadj = 1.343, 95% CI 1.063–1.695, p = 0.013), MAthrombin (ORadj = 1.106, 95% CI 1.058–1.157, p < 0.001), and fibrinogen (ORadj = 1.003, 95% CI 1.001–1.005, p = 0.012) were all independent positive predictors for HRPR. MAthrombin and fibrinogen were meaningful mediators for the significant positive association of the number of narrowed vessels and HRPR on clopidogrel, which were enhanced by around 30% and 43%, respectively, for this effect.


This is the first study to demonstrate that the positive correlation between the number of stenotic coronaries and HRPR on clopidogrel may be partly attributed to IHC, which may enhance the risk stratification, guide more precise coagulation in multi-vessel disease after drug-eluting stents, and therefore deserve further study.


Antiplatelet agents Clot strength Fibrinogen Intrinsic coagulability Three-vessel disease 



We thank the participants in the study.


This work and the Rapid Service Fee were supported by the National Natural Science Foundation of China (81300152; 81521001) and the National Key Research and Development Program of China (2016YFC1301303; 2016YFC1301302).


All authors had full access to all of the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Authorship Contributions

Xin Zhao and Hongyi Wu contributed equally to this work.


Xin Zhao, Hongyi Wu, Huajie Xu, Li Shen, Bing Fan and Junbo Ge have nothing to disclose.

Compliance with Ethics Guidelines

The protocol complied with the Declaration of Helsinki, and was approved by the hospital ethics review board (No. 2011-152, Zhongshan Hospital, Fudan University, Shanghai, China). As the registry involved de-identified data, informed consent was not required.

Data Availability

The datasets generated during and analyzed during the current study are not publicly available due to the regulations of our hospital, but are available from the corresponding author on reasonable request.

Supplementary material

12325_2019_1032_MOESM1_ESM.docx (111 kb)
Supplementary material 1 (DOCX 111 kb)


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Copyright information

© Springer Healthcare Ltd., part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan HospitalFudan UniversityShanghaiChina
  2. 2.Department of Cardiology, Jinshan HospitalFudan UniversityShanghaiChina

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