title: Procoagulant human monocytes mediate tissue factor/factor VIIa-dependent platelet-thrombus formation when exposed to flowing nonanticoagulated human blood.
abstract: Tissue factor (TF) on monocyte and macrophage surfaces is a nonproteolytic cofactor for factor VIIa (FVIIa)-induced coagulation. Monocyte-derived macrophages in atherosclerotic plaques express TF, which, after plaque disruption or rupture, may complex with FVII/VIIa from the bloodstream, resulting in activation of extrinsic coagulation. We studied the effect of TF expression on human monocytes on arterial thrombus formation in a model system of thrombogenesis. Thawed, cryopreserved human monocytes adherent to plastic coverslips were stimulated with lipopolysaccharide (0.5 microgram/mL) to express TF and subsequently exposed to flowing nonanticoagulated human blood in a parallel-plate perfusion chamber. The wall shear rate at the cell surface was 650 seconds-1, corresponding to that of average-sized coronary arteries. The stimulated monocytes elicited pronounced fibrin deposition and platelet-thrombus formation. The platelet-thrombus volume was as large as that triggered by human type III collagen fibrils under similar experimental conditions. In contrast, the monocytes elicited much more fibrin deposition than the collagen surface. However, inclusion of an anti-TF monoclonal antibody that blocks the complexation of FVII/FVIIa with TF virtually abolished the fibrin deposition (P < .03) and reduced platelet-thrombus formation by more than 70% (P < .04). Thus, arterial thrombus formation induced by stimulated monocytes was almost completely blocked by the anti-TF antibody, suggesting that inhibition of TF/FVIIa complex formation on monocytes and macrophages at sites of plaque rupture or after percutaneous transluminal coronary angioplasty procedures may reduce intravascular thrombotic complications.
authors.affiliation: Nycomed Bioreg AS, Oslo, Norway.
authors.forename: R M
authors.initials: RM
authors.lastname: Barstad
authors.forename: M J
authors.initials: MJ
authors.lastname: Hamers
authors.forename: P
authors.initials: P
authors.lastname: Kierulf
authors.forename: A B
authors.initials: AB
authors.lastname: Westvik
authors.forename: K S
authors.initials: KS
authors.lastname: Sakariassen
mesh_terms: D001779:Blood Coagulation Factors / Q000037:antagonists & inhibitors / Q000502:physiology*; D001792:Blood Platelets / Q000502:physiology*; D015942:Factor VIIa / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008070:Lipopolysaccharides; D009000:Monocytes / Q000502:physiology*; D013925:Thromboplastin / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D013927:Thrombosis / Q000209:etiology
chemical_list: D001779:Blood Coagulation Factors; D008070:Lipopolysaccharides; C045071:leukocyte procoagulant activity; D013925:Thromboplastin; D015942:Factor VIIa