A cluster of blood-based protein biomarkers reflecting coagulation relates to the burden of cerebral small vessel disease

Sanne Kuipers, L Malin Overmars, Bram van Es, Jeroen de Bresser, Esther E Bron, Imo E Hoefer, L Jaap Kappelle, Charlotte E Teunissen, Geert Jan Biessels, Saskia Haitjema

Research output: Contribution to journalArticleAcademicpeer-review


Biological processes underlying cerebral small vessel disease (cSVD) are largely unknown. We hypothesized that identification of clusters of inter-related bood-based biomarkers that are associated with the burden of cSVD provides leads on underlying biological processes. In 494 participants (mean age 67.6 ± 8.7 years; 36% female; 75% cardiovascular diseases; 25% reference participants) we assessed the relation between 92 blood-based biomarkers from the OLINK cardiovascular III panel and cSVD, using cluster-based analyses. We focused particularly on white matter hyperintensities (WMH). Nineteen biomarkers individually correlated with WMH ratio (r range: 0.16-0.27, Bonferroni corrected p-values <0.05), of which sixteen biomarkers formed one biomarker cluster. Pathway analysis showed that this biomarker cluster predominantly reflected coagulation processes. This cluster related also significantly to other cSVD manifestations (lacunar infarcts, microbleeds, and enlarged perivascular spaces), which supports generalizability beyond WMHs. To study possible causal effects of biological processes reflected by the cluster we performed a mediation analysis that showed a mediation effect of the cluster on the relation between age and WMH ratio (proportion mediated 17%), and hypertension and WMH-volume (proportion mediated 21%). In conclusion, we identified a cluster of blood-based biomarkers reflecting coagulation, that is related to manifestations of cSVD, corroborating involvement of coagulation abnormalities in the etiology of cSVD.

Original languageEnglish
Pages (from-to)1282-1293
Number of pages12
JournalJournal of Cerebral Blood Flow and Metabolism
Issue number7
Early online date27 Jan 2022
Publication statusPublished - 1 Jul 2022


  • Biomarkers
  • cerebral small vessel diseases
  • coagulation
  • proteins
  • unsupervised cluster analysis


Dive into the research topics of 'A cluster of blood-based protein biomarkers reflecting coagulation relates to the burden of cerebral small vessel disease'. Together they form a unique fingerprint.

Cite this