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Blood. 2019 Mar 21. pii: blood-2018-06-853762. doi: 10.1182/blood-2018-06-853762. [Epub ahead of print]

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

Author information

1
Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, Netherlands.
2
Department of Internal Medicine, Division of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, Netherlands.
3
Department of Pediatrics, Division of Neonatology, Leiden University Medical Center, Leiden, Netherlands.
4
Central Laboratory Animal Facility, Leiden University Medical Center, Leiden, Netherlands.
5
Department of Immunopathology, Sanquin Research-Academic Medical Center Landsteiner Laboratory, University of Amsterdam, Amsterdam, Netherlands.
6
Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, University of Bern, Switzerland and Department for BioMedical Research, University of Bern, Switzerland.
7
Department of Internal Medicine and Biochemistry, Maastricht University, Maastricht, Netherlands.
8
Department of Clinical Chemistry and Hematology, University Medical Center Utrecht, Utrecht, Netherlands.
9
Department of Early Discovery Biochemistry, Genentech Inc., South San Francisco, CA, United States.
10
Amsterdam Animal Research Center, VU University Amsterdam, Amsterdam, Netherlands.
11
Institute for Clinical Chemistry, University Hospital Eppendorf, Hamburg, Germany.
12
Department of Internal Medicine, Division of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, Netherlands; b.j.m.van_vlijmen@lumc.nl.

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 where surgical handlings were required to provoke VT. Combined inhibition of natural anticoagulants antithrombin (Serpinc1) and protein C (Proc) using small interfering (si) 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 siRNA-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 following 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 demonstrates that distinct procoagulant pathways operate in mouse VT, dependent on the triggering stimulus.

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