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

Ann Neurol. 2012 Nov;72(5):716-29. doi: 10.1002/ana.23664.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Case-Control Studies
  • Cohort Studies
  • Factor XII / genetics
  • Factor XII / metabolism
  • Female
  • Genetic Association Studies
  • Genotype
  • Humans
  • Intracranial Hemorrhages / etiology
  • Intracranial Hemorrhages / genetics
  • Male
  • Models, Genetic
  • Pharmacogenetics*
  • Polymorphism, Single Nucleotide / genetics*
  • Predictive Value of Tests
  • ROC Curve
  • Retrospective Studies
  • Spain / epidemiology
  • Stroke / drug therapy*
  • Stroke / genetics*
  • Stroke / mortality
  • Time Factors
  • Tissue Plasminogen Activator / therapeutic use*
  • Tomography, X-Ray Computed
  • alpha-Macroglobulins / genetics
  • alpha-Macroglobulins / metabolism


  • alpha-Macroglobulins
  • Factor XII
  • Tissue Plasminogen Activator