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.

Angioscopic follow-up study of coronary ruptured plaques in nonculprit lesions

“…Several IVUS studies have demonstrated that culprit lesions of ACS have a greater plaque burden than do ruptured plaques in nonculprit lesions (6 -8). In the event of a plaque rupture, a large plaque is considered to contribute to accelerated local thrombogenicity and the development of thrombosis because of the exposure of a large amount of its contents, such as tissue factor and collagen (25). Conversely, at the nonculprit plaques in smaller sized plaques, even though thrombi still remain, growth of the thrombi may be limited.…”

Non-overt disseminated intravascular coagulation in patients during treatment with antithymocyte globulin for unrelated allogeneic hematopoietic stem cell transplantation

“…11,13 In conjunction with our observation of increased levels of TF, sTM and TAT complexes in patients treated with ATG, we conclude that the underlying mechanism of nonovert DIC is a cytokine-induced release of tissue factor into the circulation. Potential sources of active tissue factor in this pathological condition could be cytokine-activated peripheral blood monocytes, 26,27 endothelial cells [28][29][30] or platelets. 31 Our finding of increased levels of sTM as a marker of endothelial activity and inury 30 indicates a cytokinetriggered disturbance of the endothelium, which may be an important factor in the induction of nonovert DIC because of ATG treatment.…”

Intravascular Ultrasound Assessment of Ulcerated Ruptured Plaques

“…When plaque rupture occurs, it exposes tissue factor and collagen, promoting thrombosis. 20 Plaque composition determines its thrombogenic potential. Tissue factor and plasminogen activator inhibitor-1 contents of vulnerable plaques are twice that of stable plaque and parallel the macrophage area.…”