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(Stroke. 2007;38:1855.)
© 2007 American Heart Association, Inc.

Original Contributions

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

Mar Castellanos, MD, PhD; Tomás Sobrino, BSc; Mónica Millán, MD; María García, MD, PhD; Juan Arenillas, MD, PhD; Florentino Nombela, MD, PhD; David Brea, BSc; Natalia Perez de la Ossa, MD; Joaquín Serena, MD, PhD; José Vivancos, MD, PhD; José Castillo, MD, PhD Antoni Dávalos, MD, PhD

From the Department of Neurology (M.C., J.S.) and Biostatistics Unit, (M.G.), Hospital Universitari Doctor Josep Trueta, Girona, Spain; the Department of Neurology (T.S., D.B., J.C.), Neurovascular Research Laboratory, Hospital Clínico Universitario, Universidad de Santiago de Compostela, Santiago de Compostela, Spain; the Department of Neurosciences (M.M., J.A., N.P.d.l.O., A.D.), Hospital Universitari Germans Trias i Pujol, Universitat Autónoma de Barcelona, Badalona, Spain; and the Department of Neurology (F.N., J.V.), Hospital Universitario de La Princesa, Madrid, Spain.

Correspondence to Dr Antoni Dávalos, Acute Stroke Unit, Department of Neurosciences, Hospital Germans Trias I Pujol, Universitat Autònoma de Barcelona, Ctra de Canyet s/n, 08916 Badalona, Spain. E-mail adavalos.germanstrias{at}gencat.net

Background and Purpose— Plasma levels of cellular fibronectin (c-Fn) 3.6 µg/mL and of matrix metalloproteinase-9 (MMP-9) 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 3.6 µg/mL were 100%, 60%, 20%, and 100%, respectively, whereas corresponding values were 92%, 74%, 26%, and 99% for MMP-9 levels 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.

Key Words: stroke • hemorrhage • thrombolytic therapy • metalloproteinases • biomarkers • blood-brain barrier

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