Molecular Signatures of Vascular Injury Are Associated With Early Growth of Intracerebral Hemorrhage

Background and Purpose— To investigate whether molecular markers of inflammation and endothelial injury are associated with early growth of intracerebral hemorrhage (ICH). Methods— In a multicenter prospective study, we determined concentrations of interleukin-6 (IL-6), tumor necrosis factor-&agr; (TNF-&agr;), matrix metalloproteinase-9 (MMP-9), and cellular fibronectin (c-Fn) in blood samples obtained on admission from 183 patients with primary hemispheric ICH of <12 hours’ duration. Patients had a neurological evaluation and a computed tomography (CT) scan performed at baseline and at 48±6 hours. Early growth of the ICH was defined as a volume increase >33% between the 2 CT examinations for ICH with a baseline volume <20 mL and >10% for ICH ≥20 mL. Clinical, radiological, and biochemical predictive factors of ICH enlargement were analyzed by logistic regression analysis. Results— Fifty-four (29.5%) patients showed a relevant early growth of ICH. High leukocyte count and fibrinogen levels, low platelet count, and intraventricular bleeding were associated with early ICH growth in bivariate analyses. Plasma concentrations of IL-6 (median [quartiles]: 19.6 [13.6; 29.9] versus 15.9 [11.5; 19.8] pg/mL), TNF-&agr; (13.5 [8.4; 30.5] versus 8.7 [4.7; 13.5] pg/mL), MMP-9 (153.3 [117.7; 204.7] versus 70.6 [47.8; 103.8] ng/mL), and c-Fn (8.8 [6.2; 12.5] versus 2.8 [1.6; 4.2] &mgr;g/mL) were significantly higher in patients with early growth of ICH (all P<0.001). C-Fn levels >6 &mgr;g/mL (OR, 92; 95%CI, 22 to 381; P<0.0001) and IL-6>24 pg/mL (OR, 16; 95%CI, 2.3 to 119; P=0.005) were independently associated with ICH enlargement in the logistic regression analysis. Conclusions— Molecular signatures of vascular injury and inflammatory markers in the early acute phase of ICH are associated with subsequent enlargement of the hematoma.

[1]  A. Dávalos,et al.  Early neurologic deterioration in intracerebral hemorrhage , 2004, Neurology.

[2]  S. Pedraza,et al.  Plasma Cellular-Fibronectin Concentration Predicts Hemorrhagic Transformation After Thrombolytic Therapy in Acute Ischemic Stroke , 2004, Stroke.

[3]  M. Margaglione,et al.  Genetic modulation of plasma fibrinogen concentrations: Possible importance of interleukin-6 , 2004, Journal of Thrombosis and Thrombolysis.

[4]  SolveigHorstmann,et al.  Profiles of Matrix Metalloproteinases, Their Inhibitors, and Laminin in Stroke Patients , 2003 .

[5]  J. Koziol,et al.  Profiles of matrix metalloproteinases, their inhibitors, and laminin in stroke patients: influence of different therapies. , 2003, Stroke.

[6]  C. Molina,et al.  Matrix metalloproteinase-9 concentration after spontaneous intracerebral hemorrhage. , 2003, Journal of neurosurgery.

[7]  J. Serena,et al.  Plasma Metalloproteinase-9 Concentration Predicts Hemorrhagic Transformation in Acute Ischemic Stroke , 2003, Stroke.

[8]  E. Lo,et al.  Blood-Brain Barrier Disruption and Matrix Metalloproteinase-9 Expression During Reperfusion Injury: Mechanical Versus Embolic Focal Ischemia in Spontaneously Hypertensive Rats , 2002, Stroke.

[9]  G. Tsurupa,et al.  Interaction of fibrin(ogen) with fibronectin: further characterization and localization of the fibronectin-binding site. , 2002, Biochemistry.

[10]  C. Kase,et al.  Molecular signatures of brain injury after intracerebral hemorrhage , 2002, Neurology.

[11]  J T Hoff,et al.  Mechanisms of Edema Formation After Intracerebral Hemorrhage: Effects of Extravasated Red Blood Cells on Blood Flow and Blood-Brain Barrier Integrity , 2001, Stroke.

[12]  A. Algra,et al.  Plasma levels of cellular fibronectin in diabetes. , 2001, Diabetes care.

[13]  J. Broderick,et al.  Role of blood clot formation on early edema development after experimental intracerebral hemorrhage. , 1998, Stroke.

[14]  R. V. Van Heertum,et al.  Perilesional blood flow and edema formation in acute intracerebral hemorrhage: a SPECT study. , 1998, Stroke.

[15]  G. Rosenberg,et al.  Metalloproteinase inhibition blocks edema in intracerebral hemorrhage in the rat , 1997, Neurology.

[16]  N. Kawai,et al.  Mechanisms of edema formation after intracerebral hemorrhage: effects of thrombin on cerebral blood flow, blood-brain barrier permeability, and cell survival in a rat model. , 1996, Journal of neurosurgery.

[17]  J. Broderick,et al.  Early hemorrhage growth in patients with intracerebral hemorrhage. , 1997, Stroke.

[18]  Takenoriyamaguchi,et al.  Enlargement of Spontaneous Intracerebral Hemorrhage , 1996 .

[19]  Haruko Yamamoto,et al.  Enlargement of spontaneous intracerebral hemorrhage. Incidence and time course. , 1996, Stroke.

[20]  R. Keep,et al.  Edema from intracerebral hemorrhage: the role of thrombin. , 1996, Journal of neurosurgery.

[21]  G. Hamann,et al.  Microvascular basal lamina antigens disappear during cerebral ischemia and reperfusion. , 1995, Stroke.

[22]  R. Kelley,et al.  Acute leukocyte and temperature response in hypertensive intracerebral hemorrhage. , 1995, Stroke.

[23]  Y. Fujii,et al.  Hematoma enlargement in spontaneous intracerebral hemorrhage. , 1994, Journal of neurosurgery.

[24]  A. Mendelow Mechanisms of ischemic brain damage with intracerebral hemorrhage. , 1993, Stroke.

[25]  J Demongeot,et al.  Formulas for threshold computations. , 1991, Computers and biomedical research, an international journal.

[26]  K. Forsyth,et al.  Fibronectin degradation; An in‐vitro model of neutrophil mediated endothelial cell damage , 1990, The Journal of pathology.

[27]  A. Woolf,et al.  Elevated plasma levels of ED1+ ("cellular") fibronectin in patients with vascular injury. , 1989, The Journal of laboratory and clinical medicine.

[28]  W. T. Chen,et al.  Transforming growth factor beta stimulates the expression of fibronectin and of both subunits of the human fibronectin receptor by cultured human lung fibroblasts. , 1988, The Journal of biological chemistry.

[29]  P. Poubelle,et al.  Fibronectin gene expression in polymorphonuclear leukocytes. Accumulation of mRNA in inflammatory cells. , 1987, The Journal of biological chemistry.

[30]  L. Zardi,et al.  Differential expression of the ED sequence-containing form of cellular fibronectin in embryonic and adult human tissues. , 1947, Journal of cell science.

[31]  M. Karplus,et al.  The dynamics of proteins. , 1982, Scientific American.