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Projeto de investigação
TROMBOSE VENOSA CELEBRAL: DA FISIOPATOLOGIA À TERAPÊUTICA
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Safety of pregnancy after cerebral venous thrombosis : a systematic review
Publication . de Sousa, Diana Aguiar; Canhão, Patrícia; Ferro, José
Background and purpose: Pregnancy and puerperium are associated with an increased risk of venous thrombotic events (VTEs), including cerebral venous thrombosis (CVT). We aimed to systematically review, in pregnant woman with previous CVT, (1) the risk of recurrence of CVT or other VTE; (2) the result of pregnancy; and (3) the association of antithrombotic prophylaxis with these outcomes.
Methods: We searched MEDLINE, Cochrane Database of Systematic Reviews, clinicaltrials.gov (from inception to July 2015), and reference lists of included studies and review articles. We considered observational studies reporting original data on the frequency of CVT or other VTE associated with pregnancy or puerperium in women with history of CVT.
Results: Thirteen studies were included. A simple pooled analysis of individual patient data and meta-analysis of proportions using a random effect model were performed. (1) 1 CVT recurrences/217 pregnancies (9 per 1000; 95% confidence interval, 3-33) and 5 noncerebral VTE/186 pregnancies (27 per 1000; 95% confidence interval, 12-61). (2) Pregnancy outcome: 33 spontaneous abortions/186 pregnancies (17.7%; 95% confidence interval, 13-24). (3) Data on the risk of CVT/extracerebral VTE according to antithrombotic prophylaxis was limited. Miscarriage did not differ significantly in women undergoing antithrombotic therapy or not (11.3% versus 18.8%; P=0.34).
Conclusions: In women with previous CVT, the absolute risk of pregnancy-related venous thrombosis is low but the relative risk of noncerebral VTE is 16-fold higher and the recurrence of CVT is 80-fold higher than the baseline risk described in general population studies. The rate of miscarriage is not significantly different from that estimated for the general population.
Matrix Metalloproteinase-9 levels are associated with brain lesion and persistent venous occlusion in patients with cerebral venous thrombosis
Publication . de Sousa, Diana Aguiar; Pereira Santos, Maria Conceição; Serra-Caetano, Ana; Lucas Neto, Lia; Sousa, Ana Luísa; Gabriel, Denis; Correia, Manuel; Gil-Gouveia, Raquel; Oliveira, Renato; Penas, Sara; Carvalho Dias, Mariana; Correia, Manuel A.; Carvalho, Marta; Sousa, Ana E.; Canhão, Patrícia; Ferro, José
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.
Cerebral venous thrombosis : from pathophysiology to therapeutics
Publication . de Sousa, Diana Aguiar; Ferro, José Manuel Morão Cabral; Canhão, Patrícia Martins
Cerebral Venous Thrombosis (CVT) is a less common form of stroke that mostly affects young women. Despite the great progress made in the last decades, significant evidence gaps persist in the understanding of the pathophysiology of brain damage, the mechanisms underlying the benefit of the available treatment strategies and the management of secondary prophylaxis. This work was focused on two of these questions, namely: (1) the mechanisms underlying the pathogenesis of brain lesion and their evolution in relation with the therapeutic intervention; and (2) the risk of pregnancy-related venous thrombotic events and unfavourable foetal outcomes in women with history of CVT, and the most appropriate approach to prevent them.
We have performed two systematic reviews (and one systematic review update) and three original studies. The available evidence was appraised in the systematic reviews and the main research gaps were identified. To further address the first aim, we have conducted a multicenter prospective cohort study of patients treated with anticoagulation that included serial standard magnetic resonance imaging and blood collection at several time-points, in order to assess early venous recanalization and biomarkers of blood-brain barrier (BBB) disruption and inflammation. We found an association between persistent venous occlusion and early worsening of brain lesions and diffusion restriction was often associated with tissue recovery in patients with early recanalization. Patients with CVT and parenchymal brain lesions had abnormal levels of matrix metalloproteinase 9 (MMP-9) and the levels of this marker of BBB disruption following treatment start were related with the early recanalization status. Patients with CVT had higher levels of Interleukin-6 (IL-6) and this was a predictor of unfavourable functional outcome at 90-days. Also, we have pooled two registries in order to describe that a MRI marker of hypoperfusion and dilated collateral circulation, the brush sign, can be identified in CVT and is associated with brain lesion and others makers of severity. For the second aim, we performed a follow-up study of women at fertile age with history of CVT and assessed recurrent venous thrombotic events and foetal outcomes, according to antithrombotic prophylaxis.
Our results add new evidence on the mechanisms of disease, providing insights into the role of early venous recanalization in the progression and recovery of brain lesions associated with CVT in patients treated with anticoagulation, and indicating new promising markers, as the brush sign, MMP-9 and IL-6. We also collected substantial evidence that support the use of antithrombotic prophylaxis to reduce the pregnancy-related venous thrombotic events and miscarriage among women with history of CVT.
Blood biomarkers associated with inflammation predict poor prognosis in cerebral venous thrombosis : a multicenter prospective observational study
Publication . de Sousa, Diana Aguiar; Pereira Santos, M. C.; Serra-Caetano, Ana; Lucas Neto, Lia; Sousa, A. L.; Gabriel, D.; Correia, M.; Gil-Gouveia, Raquel; Oliveira, Renato; Penas, Sara; Carvalho Dias, Mariana; Correia, M. A.; Carvalho, M.; Sousa, Ana E.; Canhão, Patrícia; Ferro, José
Background and purpose: Experimental studies suggest inflammation can contribute to blood barrier disruption and brain injury in cerebral venous thrombosis (CVT). We aimed to determine whether blood biomarkers of inflammation were associated with the evolution of brain lesions, persistent venous occlusion or functional outcome in patients with CVT.
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. Evaluation of neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein (CRP) concentrations in peripheral blood samples was performed at admission in 62 patients. Additional quantification of interleukin (IL)-6 was performed at day 1, 3 and 8 in 35 patients and 22 healthy controls. Standardized magnetic resonance imaging was performed at day 1, 8 and 90. Primary outcomes were early evolution of brain lesion, early recanalization and functional outcome at 90 days.
Results: Interleukin-6 levels were increased in patients with CVT with a peak at baseline. IL-6, NLR and CRP levels were not related with brain lesion outcomes or early recanalization but had a significant association with unfavourable functional outcome at 90 days (IL-6: OR = 1.28, 95% CI: 1.05-1.56, P = 0.046; NLR: OR = 1.39, 95% CI: 1.4-1.87, P = 0.014; CRP: OR = 1.756, 95% CI: 1.010-3.051, P = 0.029). Baseline IL-6 had the best discriminative capacity, with an area under the receiver operating characteristic curve to predict unfavourable functional outcome of 0.74 (P = 0.031).
Conclusions: Increased baseline levels of NLR, CRP and IL-6 may serve as new predictive markers of worse functional prognosis at 90 days in patients with CVT. No association was found between inflammatory markers and early evolution of brain lesion or venous recanalization.
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Fundação para a Ciência e a Tecnologia
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SFRH/SINTD/92677/2013