Platelet-primed interactions of coagulation and anticoagulation pathways in flow-dependent thrombus formation

Sanne L N Brouns, Johanna P van Geffen, Elena Campello, Frauke Swieringa, Luca Spiezia, René van Oerle, Isabella Provenzale, Remco Verdoold, Richard W Farndale, Kenneth J Clemetson, Henri M H Spronk, Paola E J van der Meijden, Rachel Cavill, Marijke J E Kuijpers, Elisabetta Castoldi, Paolo Simioni*, Johan W M Heemskerk

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

In haemostasis and thrombosis, platelet, coagulation and anticoagulation pathways act together to produce fibrin-containing thrombi. We developed a microspot-based technique, in which we assessed platelet adhesion, platelet activation, thrombus structure and fibrin clot formation in real time using flowing whole blood. Microspots were made from distinct platelet-adhesive surfaces in the absence or presence of tissue factor, thrombomodulin or activated protein C. Kinetics of platelet activation, thrombus structure and fibrin formation were assessed by fluorescence microscopy. This work revealed: (1) a priming role of platelet adhesion in thrombus contraction and subsequent fibrin formation; (2) a surface-independent role of tissue factor, independent of the shear rate; (3) a mechanism of tissue factor-enhanced activation of the intrinsic coagulation pathway; (4) a local, suppressive role of the anticoagulant thrombomodulin/protein C pathway under flow. Multiparameter analysis using blood samples from patients with (anti)coagulation disorders indicated characteristic defects in thrombus formation, in cases of factor V, XI or XII deficiency; and in contrast, thrombogenic effects in patients with factor V-Leiden. Taken together, this integrative phenotyping approach of platelet-fibrin thrombus formation has revealed interaction mechanisms of platelet-primed key haemostatic pathways with alterations in patients with (anti)coagulation defects. It can help as an important functional add-on whole-blood phenotyping.

Original languageEnglish
Article number11910
Pages (from-to)11910
Number of pages15
JournalScientific Reports
Volume10
Issue number1
DOIs
Publication statusPublished - 17 Jul 2020

Keywords

  • ACTIVATION
  • BLOOD-COAGULATION
  • COLLAGEN
  • CONCENTRATE
  • FIBRIN
  • GENERATION
  • HEMOSTASIS
  • PLASMA
  • PROTEIN-C
  • RESISTANCE

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