Stabilin-2 deficiency increases thrombotic burden and alters the composition of venous thrombi in a mouse model

J Thromb Haemost. 2021 Oct;19(10):2440-2453. doi: 10.1111/jth.15429. Epub 2021 Jul 19.

Abstract

Background: Stabilin-2 is an endocytic scavenger receptor that mediates the clearance of glycosaminoglycans, phosphatidylserine-expressing cells, and the von Willebrand factor-factor VIII (FVIII) complex. In a genome-wide screening study, pathogenic loss-of-function variants in the human STAB2 gene associated with an increased incidence of unprovoked venous thromboembolism (VTE). However, the specific mechanism(s) by which stabilin-2 deficiency influences the pathogenesis of VTE is unknown.

Objectives: The aim of this study was to assess the influence of stabilin-2 on deep vein thrombosis (DVT) and to characterize the underlying prothrombotic phenotype of stabilin-2 deficiency in a mouse model.

Methods: DVT was induced using the inferior vena cava (IVC) stenosis model in two independent cohorts (littermates and non-littermates) of wild-type (Stab2+/+ ) and stabilin-2 (Stab2-/- )-deficient mice. Thrombus structure and contents were quantified by immunohistochemistry. Plasma procoagulant activity was assessed and complete blood counts were performed.

Results: Incidence of thrombus formation was not altered between Stab2+/+ and Stab2-/- mice. When thrombi were formed, Stab2-/- mice developed significantly larger thrombi than Stab2+/+ controls. Thrombi from Stab2-/- mice contained significantly more leukocytes and citrullinated histone H3 than Stab2+/+ thrombi. Stab2-/- mice had increased FVIII activity. Circulating levels of monocytes and granulocytes were significantly elevated in Stab2-/- mice, and Stab2-/- mice had elevated plasma cell-free DNA 24 hours post-IVC stenosis compared to their Stab2+/+ counterparts.

Conclusions: These data suggest that stabilin-2 deficiency associates with a prothrombotic phenotype involving elevated levels of neutrophil extracellular trap-releasing leukocytes coupled with endogenous procoagulant activity, resulting in larger and qualitatively distinct venous thrombi.

Keywords: extracellular traps; factor VIII; leukocytes; receptors; scavenger; venous thrombosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Adhesion Molecules, Neuronal
  • Disease Models, Animal
  • Extracellular Traps*
  • Mice
  • Mice, Knockout
  • Thrombosis*
  • Veins
  • von Willebrand Factor

Substances

  • Cell Adhesion Molecules, Neuronal
  • Stab2 protein, mouse
  • von Willebrand Factor

Grants and funding