RT Journal Article
SR Electronic
T1 Analysis of CSF D-Dimer to Identify Intrathecal Fibrin-Driven Autoimmunity in Patients With Multiple Sclerosis
JF Neurology - Neuroimmunology Neuroinflammation
JO Neurol Neuroimmunol Neuroinflamm
FD Lippincott Williams & Wilkins
SP e1150
DO 10.1212/NXI.0000000000001150
VO 9
IS 3
A1 Martin A. Schaller-Paule
A1 Yavor Yalachkov
A1 Helmuth Steinmetz
A1 Lucie Friedauer
A1 Elke Hattingen
A1 Wolfgang Miesbach
A1 Frank Weber
A1 Konstantin Kirchmayr
A1 Jan Hendrik Schaefer
A1 Christian Foerch
YR 2022
UL http://nn.neurology.org/content/9/3/e1150.abstract
AB 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.%CV=coefficient of variation; AQP4=aquaporin-4; BBB=blood-brain barrier; CE=contrast-enhancing lesions; CIS=clinically isolated syndrome; EDSS=Expanded Disability Status Scale; IQR=interquartile range; IVMP=IV methylprednisolone; MOG=myelin oligodendrocyte glycoprotein; MS=multiple sclerosis; PPMS=primary progressive MS; RIS=radiologically isolated syndrome; RRMS=relapsing-remitting MS