The role of carrier number on the procoagulant activity of tissue factor in blood and plasma

Abstract

Tissue factor (TF) is a transmembrane glycoprotein cofactor of activated blood coagulation factor VII (FVIIa) that is required for haemostatic thrombin generation at sites of blood vessel injury. Membrane-associated TF, also detected in circulating blood, has been shown to contribute to experimental thrombus propagation at sites of localized vessel injury. It remains uncertain how TF can circulate without initiating intravascular coagulation. This study was designed to assess whether the carrier number per unit volume of TF-inducible monocytic cell line U937 or synthetic TF-carriers affected procoagulant activity, hence thrombogenic potential. Experiments were performed to characterize the effects of TF-carrier number on the kinetics of clot formation in both open and closed systems. The procoagulant activity of TF carriers was found to correlate with carrier count. TF carriers enhanced the amidolytic activity of FVIIa towards the chromogenic substrate, S-2366, as a function of carrier count. These results suggest that TF-initiated coagulation by circulating TF is kinetically limited by diffusion path lengths between TF-bearing surface. Biophysical parameters of circulating TF such as carrier count, and flow parameters of the circulation are therefore critical determinants of the procoagulant activity of circulating TF.

Phosphatidylserine index as a marker of the procoagulant phenotype of acute myelogenous leukemia cells

“…TF expression has been shown to contribute to leukemic cell procoagulant activity (2–5). Several leukemia-specific oncogenic alleles, including the pathognomonic t(15;17) translocation in AML M3, have been shown to induce overexpression of TF (6, 7).…”

Biorheology of Platelet Activation in the Bloodstream Distal to Thrombus Formation

“…We have previously shown that the physical parameter of spatial separation, defined as the cubic root of the volume per cell, provides a measure of the average linear separation between nearest neighbor cells, and dominates the control of coagulation kinetics for cells in flow. 21 Our previous work demonstrated that the spatial separation of procoagulant surfaces in the circulation, as calculated from carrier count of either TF-coated beads or TF-expressing cells, strongly correlated with their procoagulant and prothrombotic activity. 21 The results presented in the current study suggest that the probability of platelet activation in the bloodstream increases as a function of residence time distal to sites of thrombus formation.…”

“…21 Our previous work demonstrated that the spatial separation of procoagulant surfaces in the circulation, as calculated from carrier count of either TF-coated beads or TF-expressing cells, strongly correlated with their procoagulant and prothrombotic activity. 21 The results presented in the current study suggest that the probability of platelet activation in the bloodstream increases as a function of residence time distal to sites of thrombus formation. Moreover, our work suggests that activation of the coagulation factors XI and X play a key role in promoting thrombin generation, platelet activation and microaggregate formation in the bloodstream.…”

Expression of tissue factor in rabbit pulmonary artery in an acute pulmonary embolism model

“…Under normal circumstances, blood mononuclear cells and endothelial cells do not express TF. [2,3] However, under the atherosclerosis, septic shock and other pathological conditions, when vascular wall is damaged or endothelial cells are stimulated, endothelial cells can synthesize and express a large amount of TF that initiates the extrinsic coagulation pathway, causing intravascular thrombosis. [4] It is the main regulator of blood coagulation, hemostasis and thrombosis.…”