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

Background and Purpose - Plasma levels of cellular fibronectin ( c- Fn) >= 3.6 mu g/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 mu g/ 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.