- 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.
MetadatenAuthor: | Martin A. Schaller-PauleORCiDGND, Yavor Vasilev YalachkovORCiDGND, Helmuth SteinmetzORCiDGND, Lucie FriedauerORCiDGND, Elke HattingenORCiDGND, Wolfgang MiesbachORCiDGND, Frank WeberGND, Konstantin Kirchmayr, Jan Hendrik SchäferGND, Christian FörchORCiDGND |
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URN: | urn:nbn:de:hebis:30:3-844437 |
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DOI: | https://doi.org/10.1212/NXI.0000000000001150 |
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ISSN: | 2332-7812 |
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Parent Title (English): | Neurology: Neuroimmunology & Neuroinflammation |
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Publisher: | Wolters Kluwer |
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Place of publication: | Philadelphia, Pa |
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Document Type: | Article |
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Language: | English |
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Date of Publication (online): | 2022/03/08 |
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Date of first Publication: | 2022/03/08 |
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Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
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Release Date: | 2024/05/13 |
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Volume: | 9 |
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Issue: | 3, art. e1150 |
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Article Number: | e1150 |
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Page Number: | 10 |
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First Page: | 1 |
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Last Page: | 10 |
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Note: | 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. |
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HeBIS-PPN: | 519461762 |
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Institutes: | Medizin |
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Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
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Sammlungen: | Universitätspublikationen |
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Licence (German): | Creative Commons - CC BY-NC-ND - Namensnennung - Nicht kommerziell - Keine Bearbeitungen 4.0 International |
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