title: Serum cellular fibronectin and matrix metalloproteinase-9 as screening biomarkers for the prediction of parenchymal hematoma after thrombolytic therapy in acute ischemic stroke: a multicenter confirmatory study.
abstract: OBJECTIVE
  Plasma levels of cellular fibronectin (c-Fn) > or =3.6 microg/mL and of matrix metalloproteinase-9 (MMP-9) > or =140 ng/mL have been associated with parenchymal hematoma (PH) after treatment with tissue-type plasminogen activator (t-PA) in patients with acute ischemic stroke. In this prospective study, we sought to validate the predictive capacity of the preestablished cutoff values of these biomarkers for PH in a larger series of patients.
  
  
  METHODS
  We studied 134 patients treated with t-PA within 3 hours from symptom onset according to the SITS-MOST criteria (median time to infusion, 152 minutes; median National Institutes of Health Stroke Scale score, 14) in 4 university hospitals. Hemorrhagic transformation was classified according to the European-Australasian Acute Stroke Study II definitions on computed tomography scans performed 24 to 36 hours after treatment. Relevant hemorrhagic transformation was defined as hemorrhagic infarction type 2 or any PH. Serum c-Fn and MMP-9 levels were determined by an ELISA om blood samples obtained before treatment.
  
  
  RESULTS
  Cranial computed tomography showed hemorrhagic transformation in 27 patients (20%), hemorrhagic infarction in 15 (type 2 in 8 patients), and PH in 12 patients (symptomatic in 4). Serum c-Fn and MMP-9 concentrations at baseline were significantly higher in patients with relevant hemorrhagic transformation and PH than in those without (all P<0.001). The sensitivity, specificity, and positive and negative predictive values for PH by c-Fn levels > or =3.6 microg/mL were 100%, 60%, 20%, and 100%, respectively, whereas corresponding values were 92%, 74%, 26%, and 99% for MMP-9 levels > or =140 ng/mL. When both biomarkers were at levels above the cutoff points, specificity increased to 87% and the positive predictive value increased to 41%.
  
  
  CONCLUSIONS
  This prospective study confirmed the high sensitivity and negative predictive value, with retained good specificity, of c-Fn and MMP-9 for the prediction of PH in patients treated with t-PA. Development of faster analytic methods will prove the applicability of these biomarkers in routine clinical practice.
authors.affiliation: Department of Neurology, Hospital Universitari Doctor Josep Trueta, Girona, Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: Castellanos
authors.forename: Tomás
authors.initials: T
authors.lastname: Sobrino
authors.forename: Mónica
authors.initials: M
authors.lastname: Millán
authors.forename: María
authors.initials: M
authors.lastname: García
authors.forename: Juan
authors.initials: J
authors.lastname: Arenillas
authors.forename: Florentino
authors.initials: F
authors.lastname: Nombela
authors.forename: David
authors.initials: D
authors.lastname: Brea
authors.forename: Natalia
authors.initials: N
authors.lastname: Perez de la Ossa
authors.forename: Joaquín
authors.initials: J
authors.lastname: Serena
authors.forename: José
authors.initials: J
authors.lastname: Vivancos
authors.forename: José
authors.initials: J
authors.lastname: Castillo
authors.forename: Antoni
authors.initials: A
authors.lastname: Dávalos
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000097:blood; D002545:Brain Ischemia / Q000097:blood* / Q000188:drug therapy / Q000453:epidemiology; D005260:Female; D005353:Fibronectins / Q000097:blood*; D006407:Hematoma, Epidural, Cranial / Q000097:blood* / Q000188:drug therapy / Q000453:epidemiology; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000097:blood*; D008875:Middle Aged; D011237:Predictive Value of Tests; D011446:Prospective Studies; D020521:Stroke / Q000097:blood* / Q000188:drug therapy / Q000453:epidemiology; D015912:Thrombolytic Therapy / Q000009:adverse effects
chemical_list: D015415:Biomarkers; D005353:Fibronectins; D020780:Matrix Metalloproteinase 9