TY  - JOUR
A1  - Schaller-Paule, Martin A.
A1  - Yalachkov, Yavor Vasilev
A1  - Steinmetz, Helmuth
A1  - Friedauer, Lucie
A1  - Hattingen, Elke
A1  - Miesbach, Wolfgang
A1  - Weber, Frank
A1  - Kirchmayr, Konstantin
A1  - Schäfer, Jan Hendrik
A1  - Förch, Christian
T1  - Analysis of CSF D-dimer to identify intrathecal fibrin-driven autoimmunity in patients with multiple sclerosis
T2  - Neurology: Neuroimmunology & Neuroinflammation
N2  - Background and Objectives: 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.
Methods: 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 (Qalb) and CSF/plasma D-dimer quotients (QD-dimer), and corresponding CSF fibrinogen levels were determined. Final diagnoses after full evaluation and clinical data were recorded.
Results: Of 187 patients, 113 patients received a diagnosis of MS or clinically/radiologically isolated syndrome. We found increased intrathecal CSF D-dimer generation levels (QD-dimer/Qalb-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, p = 0.031). Absolute CSF D-dimer values correlated with CSF fibrinogen levels (r = 0.463; p < 0 .001) and CSF leukocytes (r = 0.273; p = 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; p = 0.026). Exploratory subgroup analyses indicated a correlation of intrathecal inflammatory activity and CSF D-dimer levels.
Discussion: 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.
Classification of Evidence: This study provides Class I evidence that CSF D-dimer levels are elevated in patients with RRMS.
Y1  - 2022
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/84443
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-844437
SN  - 2332-7812
N1  - This research project was supported by Sanofi Genzyme within the following study: “Identification of a CSF- and blood biomarker fingerprint differentiating between highly active and moderate/mild forms of multiple sclerosis” (GZ-2016-11,612). Siemens Healthineers granted discounts on INNOVANCE LOCI D-dimer test kits for use in this study.
VL  - 9
IS  - 3, art. e1150
SP  - 1
EP  - 10
PB  - Wolters Kluwer
CY  - Philadelphia, Pa
ER  -