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.
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.
Authors: Israel Fernández-Cadenas; Maite Mendióroz; Dolors Giralt; Cristina Nafria; Elena Garcia; Caty Carrera; Cristina Gallego-Fabrega; Sophie Domingues-Montanari; Pilar Delgado; Marc Ribó; Mar Castellanos; Sergi Martínez; Marimar Freijo; Jordi Jiménez-Conde; Marta Rubiera; José Alvarez-Sabín; Carlos A Molina; Maria Angels Font; Marta Grau Olivares; Ernest Palomeras; Natalia Perez de la Ossa; Maite Martinez-Zabaleta; Jaime Masjuan; Francisco Moniche; David Canovas; Carlos Piñana; Francisco Purroy; Dolores Cocho; Inma Navas; Carlos Tejero; Nuria Aymerich; Natalia Cullell; Elena Muiño; Joaquín Serena; Francisco Rubio; Antoni Davalos; Jaume Roquer; Juan Francisco Arenillas; Joan Martí-Fábregas; Keith Keene; Wei-Min Chen; Bradford Worrall; Michele Sale; Adrià Arboix; Jerzy Krupinski; Joan Montaner Journal: Stroke Date: 2017-04-14 Impact factor: 7.914
Authors: Alexander T Limkakeng; Andrew A Monte; Christopher Kabrhel; Michael Puskarich; Laura Heitsch; Ephraim L Tsalik; Nathan I Shapiro Journal: Acad Emerg Med Date: 2016-10-03 Impact factor: 3.451
Authors: Caty Carrera; Natalia Cullell; Nuria Torres-Águila; Elena Muiño; Alejandro Bustamante; Antonio Dávalos; Elena López-Cancio; Marc Ribó; Carlos A Molina; Eva Giralt-Steinhauer; Carolina Soriano-Tárraga; Marina Mola-Caminal; Jordi Jiménez-Conde; Jaume Roquer; Cristófol Vives-Bauza; Rosa Díaz Navarro; Victor Obach; Juan Francisco Arenillas; Tomás Segura; Gemma Serrano-Heras; Joan Martí-Fàbregas; Marimar Freijo; Juan Antonio Cabezas; Turgut Tatlisumak; Laura Heitsch; Laura Ibañez; Carlos Cruchaga; Jin-Moo Lee; Daniel Strbian; Joan Montaner; Israel Fernández-Cadenas Journal: Neurology Date: 2019-07-31 Impact factor: 9.910