TY - JOUR
T1 - Mouse venous thrombosis upon silencing of anticoagulants depends on tissue factor and platelets, not FXII or neutrophils
AU - Heestermans, Marco
AU - Salloum-Asfar, Salam
AU - Streef, Tom
AU - Laghmani, El Houari
AU - Salvatori, Daniela
AU - Luken, Brenda M.
AU - Zeerleder, Sacha S.
AU - Spronk, Henri M. H.
AU - Korporaal, Suzanne J.
AU - Kirchhofer, Daniel
AU - Wagenaar, Gerry T. M.
AU - Versteeg, Henri H.
AU - Reitsma, Pieter H.
AU - Renne, Thomas
AU - van Vlijmen, Bart J. M.
N1 - Funding Information:
The authors thank Sander van Tilburg, Sophie Gerhardt (Leiden University Medical Center, Leiden, The Netherlands), and René van Oerle (Maastricht University, Maastricht, The Netherlands) for technical assistance. The authors thank Charles Esmon (University of Oklahoma Health Sciences Center, Oklahoma City, OK) for providing the 59D8 antibody, David Gailani (Vanderbilt University Medical Center, Nashville, TN) for providing F11−/− mice, and Chantal Kroone (Leiden University Medical Center) for providing the TF-positive smooth muscle cells. The authors also thank Nigel Mackman (University of North Carolina, Chapel Hill, NC) for helpful discussions. T.R. acknowledges support from the German Research Society (SFB877, TP A11 and SFB841, TP B8), and a European Research Council grant (ERC-StG-2012-311575_F-12).
Publisher Copyright:
© 2019 by The American Society of Hematology
PY - 2019/5/9
Y1 - 2019/5/9
N2 - 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. Antibodymediated 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.
AB - 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. Antibodymediated 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.
KW - FACTOR-XII
KW - ACTIVATION
KW - COAGULATION
KW - HEMOSTASIS
KW - ASPIRIN
KW - MODEL
KW - MICE
KW - PREVENTION
KW - FIBRIN
U2 - 10.1182/blood-2018-06-853762
DO - 10.1182/blood-2018-06-853762
M3 - Article
C2 - 30898865
SN - 0006-4971
VL - 133
SP - 2090
EP - 2099
JO - Blood
JF - Blood
IS - 19
ER -