Cerebral Venous Sinus Thrombosis (CVST): Long-Term Single-Center Experience

CVST is a rare location of thrombosis involving Dural/ cerebral venous sinuses. It affects around 5-10 people per million population annually. It is an uncommon but life-threatening form of stroke affecting younger individuals. Therefore, identifying and treating in a timely manner is critical. Rarer thrombotic disorders like paroxysmal nocturnal hemoglobinuria (PNH) or Janus Kinase 2 (JAK2) mutation positive myeloproliferative neoplasms (MPN) can rarely present with CVST. It can also present during pregnancy for the first time. Diagnosis is often established by Computed Tomography (CT) or Magnetic Resonance Imaging (MRI). Infections, certain medication use (asparaginase or birth control pills) could lead to CVST. Patients often present with headaches, seizures or neurological deficits. Management is often with systemic anticoagulation despite intraparenchymal hemorrhage. Reducing intracranial pressure by invasive approaches is sometimes needed.https://digitalcommons.unmc.edu/surp2022/1024/thumbnail.jp

Epigenetic basis for aberrant upregulation of autoantigen genes in humans with ANCA vasculitis

Antineutrophil cytoplasmic autoantibody (ANCA) causes vascular injury that leads to small-vessel vasculitis. Patients with ANCA aberrantly express neutrophil granule–encoding genes, including 2 that encode autoantigens: proteinase 3 (PR3) and myeloperoxidase (MPO). To uncover a potential transcriptional regulatory mechanism for PR3 and MPO disrupted in patients with ANCA vasculitis, we examined the PR3 and MPO loci in neutrophils from ANCA patients and healthy control individuals for epigenetic modifications associated with gene silencing. We found that levels of the chromatin modification H3K27me3, which is associated with gene silencing, were depleted at PR3 and MPO loci in ANCA patients compared with healthy controls. Interestingly, in both patients and controls, DNA was unmethylated at a CpG island in PR3, whereas in healthy controls, DNA was methylated at a CpG island in MPO. Consistent with decreased levels of H3K27me3, JMJD3, the demethylase specific for H3K27me3, was preferentially expressed in ANCA patients versus healthy controls. In addition, we describe a mechanism for recruiting the H3K27 methyltransferase enhancer of zeste homolog 2 (EZH2) to PR3 and MPO loci mediated by RUNX3. RUNX3 message was decreased in patients compared with healthy controls, and may also be under epigenetic control. DNA methylation was increased at the RUNX3 promoter in ANCA patients. These data indicate that epigenetic modifications associated with gene silencing are perturbed at ANCA autoantigen–encoding genes, potentially contributing to inappropriate expression of PR3 and MPO in ANCA patients