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Cerebral venous thrombosis : from pathophysiology to therapeutics
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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.
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Trombose venosa cerebral Terapêutica antitrombótica Biomarcadores Recanalização Gravidez Cerebral venous thrombosis Antithrombotic treatment Biomarkers Recanalization Pregnancy Teses de doutoramento - 2020