title: Serum von Willebrand factor, matrix metalloproteinase-9, and vascular endothelial growth factor levels predict the onset of cerebral vasospasm after aneurysmal subarachnoid hemorrhage.
abstract: OBJECTIVE
  Endothelial damage and intimal proliferation occur in vasospastic cerebral arteries after subarachnoid hemorrhage (SAH). In the peripheral vasculature, endothelial damage increases intimal matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF) levels, causing neointimal proliferation. We hypothesized that serum von Willebrand factor (vWF) (a marker of endothelial cell death), MMP-9, and VEGF levels could serve as prognostic markers in predicting the occurrence of cerebral vasospasm.
  
  
  METHODS
  Venous serum vWF, MMP-9, and VEGF levels were prospectively measured daily, for 12 days or until the onset of vasospasm, for 45 consecutive patients admitted with SAH (n = 38) or admitted for elective aneurysm clipping (control subjects, n = 7). The development of transcranial Doppler flow velocities of more than 180 cm/s and/or new focal neurological deficits with angiographically confirmed vasospasm was considered the onset of vasospasm. To establish whether these markers were specific for vasospasm versus ischemia, blood samples were obtained from a concurrent group of 42 patients within 24 hours after stroke onset unrelated to SAH.
  
  
  RESULTS
  Fifty-seven percent of patients (22 of 38 patients) developed vasospasm, 4 to 11 days after SAH (median, 7 d). Mean peak serum vWF, MMP-9, and VEGF levels were increased in the SAH prevasospasm cohort, compared with the SAH nonvasospasm cohort (vWF, 5526 +/- 929 versus 4934 +/- 599 ng/ml, P = 0.01; MMP-9, 705 +/- 338 versus 438 +/- 154 ng/ml, P = 0.006; VEGF, 0.12 +/- 0.06 versus 0.06 +/- 0.06 ng/ml, P = 0.023). Mean peak vWF, MMP-9, and VEGF levels for the focal ischemia cohort (vWF, 4645 +/- 875 ng/ml, P = 0.01; MMP-9, 250 +/- 308 ng/ml, P = 0.001; VEGF, 0.03 +/- 0.04 ng/ml, P = 0.001) were markedly lower in comparison with the SAH prevasospasm cohort and were unchanged in comparison with the control cohort. vWF levels of more than 5500 ng/ml, VEGF levels of more than 0.12 ng/ml, and MMP levels of more than 700 ng/ml each independently increased the odds of subsequent vasospasm (18-, 20-, and 25-fold, respectively).
  
  
  CONCLUSIONS
  The development of cerebral vasospasm after SAH was preceded by increases in serum vWF, MMP-9, and VEGF levels. Increased serum vWF, MMP-9, and VEGF levels could accurately predict the onset of cerebral vasospasm after SAH. These factors were not elevated by SAH alone or in a separate cohort of patients with ischemic stroke, suggesting that these factors might play a role in the pathogenesis of human cerebral vasospasm.
authors.affiliation: Multidisciplinary Neuroprotection Laboratory, Medical Center, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: McGirt
authors.forename: John R
authors.initials: JR
authors.lastname: Lynch
authors.forename: Robert
authors.initials: R
authors.lastname: Blessing
authors.forename: David S
authors.initials: DS
authors.lastname: Warner
authors.forename: Allan H
authors.initials: AH
authors.lastname: Friedman
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Laskowitz
mesh_terms: D000368:Aged; D016228:Endothelial Growth Factors / Q000097:blood*; D005260:Female; D005544:Forecasting; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood*; D008222:Lymphokines / Q000097:blood*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000097:blood*; D008875:Middle Aged; D013345:Subarachnoid Hemorrhage / Q000097:blood* / Q000150:complications*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D020301:Vasospasm, Intracranial / Q000209:etiology*; D014841:von Willebrand Factor / Q000032:analysis*
chemical_list: D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014841:von Willebrand Factor; D020780:Matrix Metalloproteinase 9