PROCOAGULANT HUMAN MONOCYTES MEDIATE TISSUE FACTOR FACTOR VIIA-DEPENDENT PLATELET-THROMBUS FORMATION WHEN EXPOSED TO FLOWING NONANTICOAGULATED HUMAN BLOOD

Tissue factor (TF) on monocyte and macrophage surfaces is a nonproteol ytic cofactor for factor VIIa (FVIIa)-induced coagulation. Monocyte-de rived macrophages in atherosclerotic plaques express TF, which, after plaque disruption or rupture, may complex with FVII/VIIa from the bloo dstream, resulting in activation of extrinsic coagulation. We studied the effect of TF expression on human monocytes on arterial thrombus fo rmation in a model system of thrombogenesis. Thawed, cryopreserved hum an monocytes adherent to plastic coverslips were stimulated with lipop olysaccharide (0.5 mu g/mL) to express TF and subsequently exposed to flowing nonanticoagulated human blood in a parallel-plate perfusion ch amber. The wall shear rate at the cell surface was 650 seconds(-1), co rresponding 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 triggere d by human type III collagen fibrils under similar experimental condit ions. 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 forma tion on monocytes and macrophages at sites of plaque rupture or after percutaneous transluminal coronary angioplasty procedures may reduce i ntravascular thrombotic complications.