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Mouse venous thrombosis upon silencing of anticoagulants depends on tissue factor and platelets, not FXII or neutrophils

Marco Heestermans, Salam Salloum-Asfar, Tom Streef, El Houari Laghmani, Daniela Salvatori, Brenda M. Luken, Sacha S. Zeerleder, Henri M. H. Spronk, Suzanne J. Korporaal, Daniel Kirchhofer, Gerry T. M. Wagenaar, Henri H. Versteeg, Pieter H. Reitsma, Thomas Renné and Bart J. M. van Vlijmen

Key Points

  • Tissue factor and platelets are rate-limiting for mouse VT after inhibition of antithrombin and protein C.

  • Coagulation factor XII and circulating neutrophils are not rate-limiting in this animal model for VT.

Abstract

Tissue factor, coagulation factor XII, platelets, and neutrophils are implicated as important players in the pathophysiology of (experimental) venous thrombosis (VT). Their role became evident in mouse models in which surgical handlings were required to provoke VT. Combined inhibition of the natural anticoagulants antithrombin (Serpinc1) and protein C (Proc) using small interfering RNA without additional triggers also results in a venous thrombotic phenotype in mice, most notably with vessel occlusion in large veins of the head. VT is fatal but is fully rescued by thrombin inhibition. In the present study, we used this VT mouse model to investigate the involvement of tissue factor, coagulation factor XII, platelets, and neutrophils. Antibody-mediated inhibition of tissue factor reduced the clinical features of VT, the coagulopathy in the head, and fibrin deposition in the liver. In contrast, genetic deficiency in, and small interfering RNA–mediated depletion of, coagulation factor XII did not alter VT onset, severity, or thrombus morphology. Antibody-mediated depletion of platelets fully abrogated coagulopathy in the head and liver fibrin deposition. Although neutrophils were abundant in thrombotic lesions, depletion of circulating Ly6G-positive neutrophils did not affect onset, severity, thrombus morphology, or liver fibrin deposition. In conclusion, VT after inhibition of antithrombin and protein C is dependent on the presence of tissue factor and platelets but not on coagulation factor XII and circulating neutrophils. This study shows that distinct procoagulant pathways operate in mouse VT, dependent on the triggering stimulus.

  • Submitted June 1, 2018.
  • Accepted March 14, 2019.
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