Original Article

A predictive clinical–genetic model of tissue plasminogen activator response in acute ischemic stroke†

  1. Alberto del Río-Espínola PhD1,
  2. Israel Fernández-Cadenas PhD1,
  3. Dolors Giralt BSc1,
  4. Adoracion Quiroga BSc2,
  5. Maria Gutiérrez-Agulló MSc3,
  6. Manuel Quintana BSc4,
  7. Patricia Fernández-Álvarez MSc2,
  8. Sophie Domingues-Montanari PhD1,
  9. Maite Mendióroz MD, PhD1,
  10. Pilar Delgado MD, PhD1,
  11. Natacha Turck PhD5,
  12. Agustin Ruíz PhD6,
  13. Marc Ribó MD, PhD4,
  14. Mar Castellanos MD, PhD7,
  15. Victor Obach MD, PhD8,
  16. Sergi Martínez MD, PhD9,
  17. Mari Mar Freijo MD10,
  18. Jordi Jiménez-Conde MD, PhD11,
  19. Elisa Cuadrado-Godia MD11,
  20. Jaume Roquer MD, PhD11,
  21. Pilar Chacón PhD3,
  22. Joan Martí-Fábregas MD, PhD9,
  23. Jean Charles Sánchez PhD5,
  24. the GRECOS Investigators1,
  25. Joan Montaner MD, PhD1,‡,*

Article first published online: 27 DEC 2012

DOI: 10.1002/ana.23664

Issue

Annals of Neurology

Annals of Neurology

Volume 72, Issue 5, pages 716–729, November 2012

Additional Information

How to Cite

del Río-Espínola, A., Fernández-Cadenas, I., Giralt, D., Quiroga, A., Gutiérrez-Agulló, M., Quintana, M., Fernández-Álvarez, P., Domingues-Montanari, S., Mendióroz, M., Delgado, P., Turck, N., Ruíz, A., Ribó, M., Castellanos, M., Obach, V., Martínez, S., Freijo, M. M., Jiménez-Conde, J., Cuadrado-Godia, E., Roquer, J., Chacón, P., Martí-Fábregas, J., Sánchez, J. C., the GRECOS Investigators and Montaner, J. (2012), A predictive clinical–genetic model of tissue plasminogen activator response in acute ischemic stroke. Ann Neurol., 72: 716–729. doi: 10.1002/ana.23664

Author Information

  1. 1

    Neurovascular Research Laboratory and Neurovascular Unit, Departments of Neurology and Medicine Departments, Autonomous University of Barcelona, Spain

  2. 2

    Experimental Cardiology Research Laboratory, Vall d'Hebrón Hospital, Barcelona, Spain

  3. 3

    Lipids Unit, Department of Biochemistry, Vall d'Hebrón Hospital, Barcelona, Spain

  4. 4

    Department of Neurology, Vall d'Hebrón Hospital, Barcelona, Spain

  5. 5

    Biomedical Proteomics Research Group, Department of Structural Biology and Bioinformatics, Medical University Center, Geneva, Switzerland

  6. 6

    Department of Structural Genomics, Neocodex, Seville, Spain

  7. 7

    Department of Neurology, Dr Josep Trueta University Hospital, Girona Institute of Biomedical Investigation, Girona, Spain

  8. 8

    Stroke Unit, Department of Neurological Sciences, Hospital Clinic and August Pi i Sunyer Institute for Biomedical Investigation, University of Barcelona, Barcelona, Spain

  9. 9

    Department of Neurology, Santa Creu i Sant Pau Hospital, Barcelona, Spain

  10. 10

    Department of Neurology, Basurto Hospital, Bilbao, Spain

  11. 11

    Department of Neurology, Mar Hospital and Center for Genomic Regulation, Pompeu Fabra University, Barcelona, Spain

  1. ‡

    These authors contributed equally to the work.

*Neurovascular Research Laboratory, Institut de Recerca, Hospital Vall d'Hebron, Pg Vall d'Hebron 119-129, 08035 Barcelona, Spain

  1. †

    See the Appendix on page 13.

  2. ‡

    These authors contributed equally to the work.

Publication History

  1. Issue published online: 27 DEC 2012
  2. Article first published online: 27 DEC 2012
  3. Accepted manuscript online: 9 JUN 2012 10:49AM EST
  4. Manuscript Accepted: 1 JUN 2012
  5. Manuscript Revised: 29 MAY 2012
  6. Manuscript Received: 27 DEC 2011

Funded by

  • Neurovascular Research Laboratory receives grants
  • Spanish Stroke Research Network. Grant Number: RENEVAS, RD06/0026/0010
  • European Stroke Network. Grant Number: EUSTROKE 7FP Health F2-08-202213
  • Spanish government. Grant Number: FIS PJ060586
  • Ramón Areces Foundation. Grant Number: 2006

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Abstract

Objective:

Wide interindividual variability exists in response to tissue plasminogen activator (t-PA) treatment in the acute phase of ischemic stroke. We aimed to find genetic variations associated with hemorrhagic transformation (HT) and mortality rates after t-PA. We then generated a clinical–genetic model for predicting t-PA response.

Methods:

Our prospective study used SNPlex to genotype 140 single nucleotide polymorphisms (SNPs) from 97 candidate genes in 3 patient cohorts. The cohorts included 1,172 patients who were treated with t-PA; 20.9% of them developed HT as evaluated by systematic brain computed tomography scan, and 10.6% died. A predictive model was generated by logistic regression (LR). Functional studies included real time quantitative polymerase chain reaction, nephelometry, and Western blot for alpha-2-macroglobulin (A2M) and activated partial thromboplastin time measurement for coagulation factor XII (FXII).

Results:

Replication analysis revealed that the SNP rs669 (Val1000Ile) in A2M was associated with HT, and rs1801020 (−4C>T) of F12 was associated with in-hospital death. The rs669 SNP withstood Bonferroni correction for HT (p < 3.57E−4). LR-based scores predicted HT occurrence (p = 9.13E−15) and in-hospital mortality (p = 8.7E−9) and were validated in an independent cohort. Val1000Ile modified A2M serum levels at baseline and after t-PA infusion, but not mRNA expression or protein structure; −4C>T affected FXII activity both prior to and after t-PA treatment.

Interpretation:

Two functional polymorphisms were consistently associated with t-PA safety. Our validated LR-based score predicts t-PA safety in the Spanish population. ANN NEUROL 2012;72:716–729

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