title: Role of platelets, neutrophils, and factor XII in spontaneous venous thrombosis in mice.
abstract: Recently, platelets, neutrophils, and factor XII (FXII) have been implicated as important players in the pathophysiology of venous thrombosis. Their role became evident in mouse models in which surgical handling was used to provoke thrombosis. Inhibiting anticoagulation in mice by using small interfering RNA (siRNA) targeting Serpinc1 and Proc also results in a thrombotic phenotype, which is spontaneous (no additional triggers) and reproducibly results in clots in the large veins of the head and fibrin deposition in the liver. This thrombotic phenotype is fatal but can be fully rescued by thrombin inhibition. The mouse model was used in this study to investigate the role of platelets, neutrophils, and FXII. After administration of siRNAs targeting Serpinc1 and Proc, antibody-mediated depletion of platelets fully abrogated the clinical features as well as microscopic aspects in the head. This was corroborated by strongly reduced fibrin deposition in the liver. Whereas neutrophils were abundant in siRNA-triggered thrombotic lesions, antibody-mediated depletion of circulating Ly6G-positive neutrophils did not affect onset, severity, or thrombus morphology. In addition, absence of circulating neutrophils did not affect quantitative liver fibrin deposition. Remarkably, siRNA-mediated depletion of plasma FXII accelerated the onset of the clinical phenotype; mice were affected with more severe thrombotic lesions. To summarize, in this study, onset and severity of the thrombotic phenotype are dependent on the presence of platelets but not circulating neutrophils. Unexpectedly, FXII has a protective effect. This study challenges the proposed roles of neutrophils and FXII in venous thrombosis pathophysiology.
authors.affiliation: Einthoven Laboratory for Experimental Vascular Medicine, Department of Internal Medicine, Division of Thrombosis and Hemostasis.
authors.forename: Marco
authors.initials: M
authors.lastname: Heestermans
authors.affiliation: Einthoven Laboratory for Experimental Vascular Medicine, Department of Internal Medicine, Division of Thrombosis and Hemostasis.
authors.forename: Salam
authors.initials: S
authors.lastname: Salloum-Asfar
authors.affiliation: Central Laboratory Animal Facility, and.
authors.forename: Daniela
authors.initials: D
authors.lastname: Salvatori
authors.affiliation: Department of Pediatrics, Division of Neonatology, Leiden University Medical Center, Leiden, The Netherlands;
authors.forename: El Houari
authors.initials: el H
authors.lastname: Laghmani
authors.affiliation: Department of Immunopathology, Sanquin-Academic Medical Center Landsteiner Laboratory, Amsterdam, The Netherlands;
authors.forename: Brenda M
authors.initials: BM
authors.lastname: Luken
authors.affiliation: Department of Immunopathology, Sanquin-Academic Medical Center Landsteiner Laboratory, Amsterdam, The Netherlands;
authors.forename: Sacha S
authors.initials: SS
authors.lastname: Zeerleder
authors.affiliation: Department of Internal Medicine and Biochemistry, Maastricht University, Maastricht, The Netherlands; and.
authors.forename: Henri M H
authors.initials: HM
authors.lastname: Spronk
authors.affiliation: Department of Clinical Chemistry and Hematology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Suzanne J
authors.initials: SJ
authors.lastname: Korporaal
authors.affiliation: Department of Pediatrics, Division of Neonatology, Leiden University Medical Center, Leiden, The Netherlands;
authors.forename: Gerry T M
authors.initials: GT
authors.lastname: Wagenaar
authors.affiliation: Einthoven Laboratory for Experimental Vascular Medicine, Department of Internal Medicine, Division of Thrombosis and Hemostasis.
authors.forename: Pieter H
authors.initials: PH
authors.lastname: Reitsma
authors.affiliation: Einthoven Laboratory for Experimental Vascular Medicine, Department of Internal Medicine, Division of Thrombosis and Hemostasis.
authors.forename: Bart J M
authors.initials: BJ
authors.lastname: van Vlijmen
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D000990:Antithrombin III / Q000037:antagonists & inhibitors / Q000378:metabolism; D001792:Blood Platelets / Q000378:metabolism* / Q000473:pathology; D005174:Factor XII / Q000378:metabolism*; D005260:Female; D005337:Fibrin / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009504:Neutrophils / Q000378:metabolism* / Q000473:pathology; D034741:RNA, Small Interfering / Q000494:pharmacology; D020246:Venous Thrombosis / Q000378:metabolism* / Q000473:pathology
chemical_list: D000950:Antigens, Ly; C480309:Ly6G antigen, mouse; D034741:RNA, Small Interfering; D000990:Antithrombin III; D005174:Factor XII; D005337:Fibrin