Matrix Metalloproteinase-9 Levels are Associated with Brain Lesion and Persistent Venous Occlusion in Patients with Cerebral Venous Thrombosis

Abstract

Background Elucidating mechanisms of brain damage in cerebral venous thrombosis (CVT) would be instrumental to develop targeted therapies and improve prognosis prediction. Matrix metalloproteinase-9 (MMP-9), a gelatinase that degrades major components of the basal lamina, has been associated to blood–brain barrier disruption. We aimed to assess, in patients with CVT, the temporal change in serum concentrations of MMP-9 and its association with key imaging and clinical outcomes.

Methods Pathophysiology of Venous Infarction—PRediction of InfarctiOn and RecanalIzaTion in CVT (PRIORITy-CVT) was a multicenter prospective cohort study of patients with newly diagnosed CVT. Serial collection of peripheral blood samples performed on day 1, 3, and 8, and standardized magnetic resonance imaging on day 1, 8, and 90. MMP-9 was quantified using enzyme-linked immunosorbent assay in 59 patients and 22 healthy controls. Primary outcomes were parenchymal brain lesion, early evolution of brain lesion, early recanalization, and functional outcome on day 90.

Results CVT patients with parenchymal brain lesion had higher baseline concentrations of MMP-9 compared with controls (adjusted p = 0.001). The area under receiver operating characteristic curve value for MMP-9 for predicting brain lesion was 0.71 (95% confidence interval [CI]: 0.57–0.85, p = 0.009). Patients with venous recanalization showed early decline of circulating MMP-9 and significantly lower levels on day 8 (p = 0.021). Higher MMP-9 on day 8 was associated with persistent venous occlusion (odds ratio: 1.20 [per 20 ng/mL], 95% CI: 1.02–1.43, p = 0.030).

Conclusion We report a novel relationship among MMP-9, parenchymal brain damage, and early venous recanalization, suggesting that circulating MMP-9 is a dynamic marker of brain tissue damage in patients with CVT.

Keywords

cerebral venous thrombosis - blood–brain barrier - infarction - recanalization - prognosis

• References

• 1 Ferro JM, Canhão P, Stam J, Bousser MG, Barinagarrementeria F. ISCVT Investigators. Prognosis of cerebral vein and dural sinus thrombosis: results of the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT). Stroke 2004; 35 (03) 664-670
• 2 Tsai FY, Wang AM, Matovich VB. et al. MR staging of acute dural sinus thrombosis: correlation with venous pressure measurements and implications for treatment and prognosis. Am J Neuroradiol 1995; 16 (05) 1021-1029
• 3 Aguiar de Sousa D, Lucas Neto L, Arauz A. et al. Early recanalization in patients with cerebral venous thrombosis treated with anticoagulation. Stroke 2020; 51 (04) 1174-1181
• 4 Vosko MR, Röther J, Friedl B, Bültemeier G, Kloss CUA, Hamann GF. Microvascular damage following experimental sinus-vein thrombosis in rats. Acta Neuropathol 2003; 106 (05) 501-505
• 5 Kim DE, Schellingerhout D, Jaffer FA, Weissleder R, Tung CH. Near-infrared fluorescent imaging of cerebral thrombi and blood-brain barrier disruption in a mouse model of cerebral venous sinus thrombosis. J Cereb Blood Flow Metab 2005; 25 (02) 226-233
• 6 Rashad S, Niizuma K, Sato-Maeda M. et al. Early BBB breakdown and subacute inflammasome activation and pyroptosis as a result of cerebral venous thrombosis. Brain Res 2018; 1699: 54-68
• 7 Nguyen KP, McGilvray KC, Puttlitz CM, Mukhopadhyay S, Chabasse C, Sarkar R. Matrix metalloproteinase 9 (MMP-9) regulates vein wall biomechanics in murine thrombus resolution. PLoS One 2015; 10 (09) e0139145
• 8 Yoshimoto Y, Endo M, Mori T, Wakai S. Correlation between venous stump pressure and brain damage after cortical vein occlusion: an experimental study. J Neurosurg 1997; 86 (04) 694-698
• 9 Barr TL, Latour LL, Lee KY. et al. Blood-brain barrier disruption in humans is independently associated with increased matrix metalloproteinase-9. Stroke 2010; 41 (03) e123-e128
• 10 Montaner J, Molina CA, Monasterio J. et al. Matrix metalloproteinase-9 pretreatment level predicts intracranial hemorrhagic complications after thrombolysis in human stroke. Circulation 2003; 107 (04) 598-603
• 11 Lee CZ, Xue Z, Zhu Y, Yang GY, Young WL. Matrix metalloproteinase-9 inhibition attenuates vascular endothelial growth factor-induced intracerebral hemorrhage. Stroke 2007; 38 (09) 2563-2568
• 12 Svedin P, Hagberg H, Sävman K, Zhu C, Mallard C. Matrix metalloproteinase-9 gene knock-out protects the immature brain after cerebral hypoxia-ischemia. J Neurosci 2007; 27 (07) 1511-1518
• 13 Chaturvedi M, Kaczmarek L. Mmp-9 inhibition: a therapeutic strategy in ischemic stroke. Mol Neurobiol 2014; 49 (01) 563-573