Tissue factor activity in human monocytes is regulated by plasma: implications for the high and low responder phenomenon

Abstract

Summary. The`high and low responder phenomenon' of monocyte tissue factor (MTF) activity has been attributed to effects on monocytes by granulocytes, platelets and lipopolysaccharide (LPS). To study the possible contribution of plasma to the high and low responder phenomenon, we measured the MTF activity in isolated cryopreserved human monocytes from two donors (monocytes A and monocytes B) after incubation in a plasma environment depleted of granulocytes, platelets and LPS. In buffer only, MTF activity was 643 and 679 fM (fM final concentration of tissue factor), in normal pooled plasma, it was 1478 and 1615 fM (P 0´001), respectively, in monocytes A and in monocytes B. Incubation with individual plasma samples from healthy controls (n 43) gave a median MTF of 1355 fM (range 1044±1976 fM) and 1329 fM (range 858±1951 fM) respectively. A plasma consistently induced a higher or lower level of MTF activity in both monocytes: r 0´82 (P , 0´00001). Coumarin use did not influence the high and low responder phenomenon. In the absence of granulocytes, platelets and LPS, plasma determines the high and low responder phenomenon. This phenomenon is not influenced by coumarin treatment.

Prothrombin activation in blood coagulation: the erythrocyte contribution to thrombin generation

“…21 WBCs have been reported to display a procoagulant phenotype in the context of ischemic vascular disease 22 and sepsis via expression of Tf. [23][24][25] Enzymatic complexes bound to monocytes and neutrophils exhibit IIasebinding values similar to the platelet-bound complex; however, Thrombin-and meizothrombin-generation parameters are from Figure 6. The clot time, maximum (max) rate of ␣TAT and mTAT formation and max level of ␣TAT and mTAT formation were calculated from the ␣TAT and mTAT ELISA data.…”

Induction of microparticle- and cell-associated intravascular tissue factor in human endotoxemia

“…We believe this finding represents the in vivo analog of the previously described "high versus low responder" phenotype phenomenon, which is used to describe the variable monocyte responsiveness to LPS in whole blood in vitro. [40][41][42] The precise explanation for this phenomenon is unclear, but may reflect individual differences in plasma, 40 leukocyte, 42 or platelet 58 factors. The absolute increase in TF activity in peripheral blood monocytes was demonstrated to have prognostic significance in meningococcal sepsis, with higher levels portending a poorer outcome.…”

“…Since monocytes are presumably the sole source of inducible activity, the variability in MP-borne TF response to LPS is seemingly analogous to the previously described variability in monocyte-borne TF, which has been termed the "high/low LPS responder phenomenon." [40][41][42] On repeated testing, we found the MP tissue factor …”

Coagulation Abnormalities in Acute Pancreatitis

“…After damage to the endothelial wall, however, TF is exposed to blood where it is free to bind plasma factor VIIa, forming TF-factor VIIa complex. TF is also expressed by macrophages and monocytes after stimulation by inflammatory mediators (Esmon, 1999;Nijziel et al, 2001;Bouchard & Tracy, 2003) Tissue factor (TF) forms a complex with a small amount of circulating activated factor VII (FVIIa) and acts as a cofactor for increasing the ability of FVIIa to convert FX to FXa and FIX to FIXa at the cell surface (Osterud et al, 1978). FXa activates FV and together they convert a small amount of prothrombin to thrombin (Monroe et al, 1996).…”