Analysis of CSF D-Dimer to Identify Intrathecal Fibrin-Driven Autoimmunity in Patients With Multiple Sclerosis
Martin A. Schaller-Paule, Yavor Yalachkov, Helmuth Steinmetz, Lucie Friedauer, Elke Hattingen, Wolfgang Miesbach, Frank Weber, Konstantin Kirchmayr, Jan Hendrik Schaefer, Christian Foerch
Abstract
<h3>Background and Objectives</h3> Proteins of the coagulation system contribute to autoimmune inflammation in patients with multiple sclerosis (MS). On blood-brain barrier (BBB) disruption, fibrinogen enters the CNS and is rapidly converted to fibrin, unfolding pleiotropic autoimmune mechanisms. Fibrin accumulation leads to subsequent proteolytic degradation that results in D-dimer generation. The primary objective of this study was to determine intrathecal levels of D-dimer in CSF as a measure of intrathecal coagulation cascade activation and to evaluate its diagnostic utility in patients with MS in contrast to healthy subjects. Key secondary objectives included analysis of CSF D-dimer in differential diagnoses of MS and its relation to routine clinical markers of disease activity. <h3>Methods</h3> Patients admitted for the assessment of suspected MS were prospectively recruited from October 2017 to December 2020. Blood plasma and citrated CSF samples were analyzed using a highly sensitive luminescent oxygen channeling immunoassay. Intrathecal generation of D-dimer was analyzed by adjusting for CSF/serum albumin (Q<sub>alb</sub>) and CSF/plasma D-dimer quotients (Q<sub>D-dimer</sub>), and corresponding CSF fibrinogen levels were determined. Final diagnoses after full evaluation and clinical data were recorded. <h3>Results</h3> Of 187 patients, 113 patients received a diagnosis of MS or clinically/radiologically isolated syndrome. We found increased intrathecal CSF D-dimer generation levels (Q<sub>D-dimer</sub>/Q<sub>alb</sub>-index) for patients with relapsing-remitting MS (RRMS; n = 71, median 4.7, interquartile range [IQR] 2.5–8.0) when compared with those for disease controls (n = 22, median 2.6, IQR 2.1–4.8, <i>p</i> = 0.031). Absolute CSF D-dimer values correlated with CSF fibrinogen levels (r = 0.463; <i>p</i> < 0 .001) and CSF leukocytes (r = 0.273; <i>p</i> = 0.003) and were elevated in MS patients with contrast enhancement (CE) compared with MS patients without CE on MRI (n = 48, median 6 ng/mL, and IQR 3–15.25 vs n = 41, median 4 ng/mL, and IQR 2–7; <i>p</i> = 0.026). Exploratory subgroup analyses indicated a correlation of intrathecal inflammatory activity and CSF D-dimer levels. <h3>Discussion</h3> D-dimer in CSF can be reliably determined and correlates with markers of CNS inflammation and CSF fibrinogen levels. Adjusted for BBB dysfunction, CSF D-dimer may allow the identification of intrathecal coagulation cascade activation in patients with MS. <h3>Classification of Evidence</h3> This study provides Class I evidence that CSF D-dimer levels are elevated in patients with RRMS.