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

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.