Correlation between ADAMTS13 and VAP1 levels in Multiple Sclerosis with cerebral microbleeds

Background: The progressive failure of blood–brain barrier (BBB) integrity, which may have the pathological feature of cerebral microbleeds (CMBs), leads to focal extravascular leakage of blood components and subsequently induces several inflammatory responses. CMBs have been associated with worsening of physical and cognitive disability in multiple sclerosis (MS). Adhesion molecules, which participate in BBB disruption and in inflammatory responses, could be involved in the formation of CMBs. The anti-inflammatory properties of hemostasis inhibitors offer a rational link for their study in the presence of CMBs. Aims: To explore plasma levels, and correlations of hemostasis inhibitors and adhesion molecules in relation to CMBs in MS. Methods: Plasma levels of coagulation inhibitors (PC, TM, EPCR, PS, TFPI, HCII, ADAMTS13, PAI1) and soluble adhesion molecules (sNCAM, sICAM1, sVCAM1, sVAP1), were evaluated by Multiplex and ELISA in 125 MS patients and 42 healthy individuals (HI) who underwent 3T MRI exams. CMBs were assessed on susceptibility-weighted minimum intensity projection images and susceptibility maps. Spearman’s correlation and Mann–Whitney test were used, as appropriate. Results: Patients with CMBs (n=12) showed, in addition to significantly lower ADAMTS13 levels (p=0.025), significantly higher sNCAM levels (p=0.017) and a trend for higher levels of VAP1 compared to MS patients without CMBs (n=113). Only in MS with CMBs, ADAMSTS13-VAP1 levels were correlated (r=0.67, p=0.020). In MS with CMBs and in HI, levels of PAI1-sVCAM1 were correlated (r=0.73, p=0.009 and r=0.33, p=0.031). Conclusions: With the limitation of the low number of patients with CMBs, our findings suggest an intriguing molecular relationship between adhesion molecules and hemostasis inhibitors in development of CMBs in MS. The reactive oxygen species produced by VAP-1, an inflammatory adhesion molecule endowed with enzymatic properties, could interfere with ADAMTS13/von Willebrand factor function, a hypothesis that deserves further investigation