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Carboxypeptidase U (TAFIa) Is Rapidly Activated and Deactivated Following Thrombolysis and Thrombectomy in Stroke Patients

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Abstract

The antifibrinolytic enzyme carboxypeptidase U (CPU, TAFIa, CPB2) is an appealing target for the treatment of acute ischemic stroke (AIS). Increased insights in CPU activation and inactivation during thrombolysis (rtPA) with or without endovascular thrombectomy (EVT) are required to develop CPU inhibitors as profibrinolytic agents with optimal benefits/risks. Therefore, CPU kinetics during ischemic stroke treatment were evaluated. AIS patients with documented cerebral artery occlusion receiving rtPA (N = 20) or rtPA + EVT (N = 16) were included. CPU activation during thrombolysis was measured by an ultrasensitive HPLC-based CPU activity method and by an ELISA measuring both CPU and inactivated CPU (CPU + CPUi). Intravenous blood samples were collected at admission and throughout the first 24 h. Additional in situ blood samples were collected in the rtPA + EVT cohort proximal from the thrombus. The NIHSS score was determined at baseline and 24 h. CPU activity and CPU + CPUi levels increased upon rtPA administration and reached peak values at the end of thrombolysis (1 h). High inter-individual variability was observed in both groups. CPU activity decreased rapidly within 3 h, while CPU + CPUi levels were still elevated at 7 h. CPU activity or CPU + CPUi levels were similar in in situ and peripheral samples. No correlation between CPU or CPU + CPUi and NIHSS or thrombus localization was found. The CPU system was rapidly activated and deactivated following thrombolysis and thrombectomy in stroke patients, suggesting that a CPU inhibitor would have to be administered during rtPA infusion and over the next few hours. The high CPU generation variability suggests that some patients may not respond to the treatment. EudraCT number 2017-002760-41.

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Data Availability

Anonymized patient-level, study-level clinical trial data (including clinical study report) and study protocol, underlying the results reported in this article will be shared in agreement with the Servier Data Sharing Policy available at https://clinicaltrials.servier.com/data-request-portal/.

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Acknowledgements

The authors thank Y. Sim and L. Saudemont for their excellent technical assistance.

Funding

The study was funded by the Institut de Recherches Internationales Servier (IRIS, Paris, France). J.M. was a research fellow of the Research Foundation Flanders during the conduct of the study (grant: 1137719 N).

Author information

Authors and Affiliations

  1. Laboratory of Medical Biochemistry, University of Antwerp, Antwerp, Belgium

    Joachim C. Mertens, Karen Claesen & Dirk Hendriks

  2. Cardiovascular and Metabolic Diseases Center for Therapeutic Innovation, Institut de Recherches Internationales Servier, Suresnes Cedex, France

    Vanessa Blanc-Guillemaud & Benoit Tyl

  3. Department of Neurology, Hospital de Bellvitge, Hospitalet de Llobregat-Barcelona, Spain

    Pere Cardona

  4. Stroke Unit, Neurology Department, Vall d’Hebron University Hospital, Barcelona, Spain

    Carlos A. Molina

  5. Departament de Medicina, Universitat Autónoma de Barcelona, Barcelona, Spain

    Carlos A. Molina

Authors
  1. Joachim C. Mertens
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  2. Vanessa Blanc-Guillemaud
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  4. Pere Cardona
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  7. Carlos A. Molina
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Contributions

Methodology: V.B.G., D.H., B.T., C.M., J.M.; formal analysis: J.M., V.B.G.; writing—original draft preparation: J.M., V.B.G., B.T.; writing—review and editing: all authors.

Corresponding author

Correspondence to Vanessa Blanc-Guillemaud.

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Ethics Approval

The study was conducted according to the Declaration of Helsinki revised in Fortaleza and followed the Good Clinical Practices. Ethical approval was obtained from the respective ethics committees of the different centers and the study was approved by the competent authorities.

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All patients or their legal representatives gave their informed consent before participating in the trial.

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Not applicable.

Conflicts of Interest

VBG and BT are employees of IRIS. DH received consultant honoraria from IRIS.

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Mertens, J.C., Blanc-Guillemaud, V., Claesen, K. et al. Carboxypeptidase U (TAFIa) Is Rapidly Activated and Deactivated Following Thrombolysis and Thrombectomy in Stroke Patients. Transl. Stroke Res. 13, 959–969 (2022). https://doi.org/10.1007/s12975-021-00962-w

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  • DOI: https://doi.org/10.1007/s12975-021-00962-w

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