Recombinant Tissue Plasminogen Activator Induces Neurological Side Effects Independent on Thrombolysis in Mechanical Animal Models of Focal Cerebral Infarction: A Systematic Review and Meta-Analysis

• Published in: PloS one 2016-07, Vol.11 (7), p.e0158848
• Main Authors: Dong, Mei-Xue, Hu, Qing-Chuan, Shen, Peng, Pan, Jun-Xi, Wei, You-Dong, Liu, Yi-Yun, Ren, Yi-Fei, Liang, Zi-Hong, Wang, Hai-Yang, Zhao, Li-Bo, Xie, Peng
• Format: Article
• Language: English
• Subjects: Analysis; Animal models; Animals; Animals, Genetically Modified; Biology and Life Sciences; Blood-brain barrier; Blood-Brain Barrier - drug effects; Brain Edema - chemically induced; Brain Edema - complications; Care and treatment; Cerebral infarction; Cerebral Infarction - complications; Cerebral Infarction - drug therapy; Collaboration; Data Interpretation, Statistical; Disease Models, Animal; Drug dosages; Edema; Fibrinolytic agents; Free radicals; Hemorrhage; Hospitals; Identification methods; Infarction; Ischemia; Laboratories; Male; Medical ethics; Medical prognosis; Medicine and Health Sciences; Meta-analysis; Mortality; Neurobiology; Neurology; Neurosciences; People and Places; Physical Sciences; Rats; Recombinant Proteins - adverse effects; Recombinant Proteins - therapeutic use; Regression analysis; Research and Analysis Methods; Researchers; Rodents; Sensitivity analysis; Sensitivity and Specificity; Side effects; Stroke; Stroke - complications; Stroke - drug therapy; Subgroups; Systematic review; t-Plasminogen activator; Test procedures; Thrombolysis; Thrombolytic Therapy - adverse effects; Tissue plasminogen activator; Tissue Plasminogen Activator - adverse effects; Tissue Plasminogen Activator - therapeutic use; Transgenic animals; Traumatic brain injury
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0158848

Recombinant tissue plasminogen activator (rtPA) is the only effective drug approved by US FDA to treat ischemic stroke, and it contains pleiotropic effects besides thrombolysis. We performed a meta-analysis to clarify effect of tissue plasminogen activator (tPA) on cerebral infarction besides its thrombolysis property in mechanical animal stroke. Relevant studies were identified by two reviewers after searching online databases, including Pubmed, Embase, and ScienceDirect, from 1979 to 2016. We identified 6, 65, 17, 12, 16, 12 and 13 comparisons reporting effect of endogenous tPA on infarction volume and effects of rtPA on infarction volume, blood-brain barrier, brain edema, intracerebral hemorrhage, neurological function and mortality rate in all 47 included studies. Standardized mean differences for continuous measures and risk ratio for dichotomous measures were calculated to assess the effects of endogenous tPA and rtPA on cerebral infarction in animals. The quality of included studies was assessed using the Stroke Therapy Academic Industry Roundtable score. Subgroup analysis, meta-regression and sensitivity analysis were performed to explore sources of heterogeneity. Funnel plot, Trim and Fill method and Egger's test were obtained to detect publication bias. We found that both endogenous tPA and rtPA had not enlarged infarction volume, or deteriorated neurological function. However, rtPA would disrupt blood-brain barrier, aggravate brain edema, induce intracerebral hemorrhage and increase mortality rate. This meta-analysis reveals rtPA can lead to neurological side effects besides thrombolysis in mechanical animal stroke, which may account for clinical exacerbation for stroke patients that do not achieve vascular recanalization with rtPA.