Correlation between Protein C and CCL18 levels in Multiple Sclerosis

Background: Several studies suggest the crosstalk of coagulation with inflammation and immunity in the pathogenesis of multiple sclerosis (MS). Concentration of hemostasis inhibitors, which are known to possess anti-inflammatory properties, could influence this network and be associated with neurodegenerative processes. Aims: To estimate plasma levels, and level correlations of hemostasis inhibitors, inflammatory/immunomodulatory- and adhesion molecules in relation to MS disease. Methods: 138 MS patients and 42 healthy individuals (HI) were assessed with 3T MRI. Plasma levels of coagulation inhibitors (PC, TM, EPCR, PS, TFPI, HCII, ADAMTS13, PAI1), of chemokines (CCL5, CCL18), and soluble adhesion molecules (sNCAM, sICAM1, sVCAM1, sVAP1), assayed by Multiplex and ELISA, were analyzed by partial correlation. Association of protein levels with MRI outcomes was performed by regression analysis. Results: In both MS patients and HI, levels of PC-CCL18 (r=0.31, p<0.001; r=0.46, p=0.004), PC-PAI1 (r=0.27, p=0.002; r=0.41, p=0.009), PC-TFPI (r=0.21, p=0.014; r=0.46, p=0.003), and PAI1-CCL5 (r=0.55, p<0.001; r=0.56, p<0.001) were correlated. Only in HI, levels of PC-PS (r=0.43, p=0.005), PS-PAI1 (r=0.41, p=0.008), PS-VAP1 (r=0.41, p=0.009) and PS-sVCAM1 (r=0.45, p=0.004) were correlated. Only in MS patients, levels of TM were positively correlated with adhesion molecules, particularly with sICAM1 (r=0.31, p<0.001), suggesting release from membranes caused by endothelial “injury”/alteration. Increased PC levels were associated with decreased volumes of brain parenchyma (p=0.026), total gray matter (GMV) (p=0.003), cortex (CV) (p=0.008), deep gray matter (DGMV) (p=0.009), thalamus (p=0.007). Increased CCL18 levels were also associated with decreased volumes of CV (p=0.01), DGMV (p=0.006), thalamus (p=0.007). Regression model including both PC and CCL18 showed that PC explains greater variance of GM-related volumes (i.e DGMV, PC p=0.001, CCL18 p=0.052). Conclusions: Several correlation differences suggest disease-associated dysregulation of PC pathway components in MS patients. Taking into account that CCL18 is involved in immune cell chemotaxis, the correlation of PC with CCL18, both associated with neurodegeneration, suggests a novel hemostasis-immune network, warranting further investigation