Human alternatively spliced tissue factor is not secreted and does not trigger coagulation

Abstract

1-74) in patients (n = 68) with normal MP-TF activity (P = 0.028). In the group of 51 patients who presented with VTE, survival was significantly worse in patients with elevated MP-TF activity than in those with normal MP-TF activity (P = 0.010). In univariate analysis only tumour type, thrombosis and MP-TF activity were significantly associated with survival. In multivariate analysis, adjustment for tumour type, age and stage, did not affect the association between MP-TF activity and mortality (P < 0.015).The present study is the largest series of unselected patients with both cancer and VTE, in whom MP-TF activity has been measured in the acute phase of thrombosis. The strength of the present study is that we did not select for any tumour type but instead investigated all cancer patients who presented with acute VTE irrespective of the type of malignancy. We observed that MP-TF activity in cancer patients with VTE is higher than in matched cancer patients without VTE. This finding strongly supports previous observations of a relationship between elevated MP-TF activity and VTE in patients with cancer from small studies of selected cancer patients [1,[4][5][6].It is interesting that the large majority of patients who develop VTE during chemotherapy have normal MP-TF activity, suggesting that an acute thrombotic event itself is not the cause of an elevated MP-TF activity. Our data point to a contribution of cancer cells themselves as (in) direct cause of elevated MP-TF activity and ask for novel studies better designed to study prospectively the relationship between chemotherapy, elevated MP-TF activity and venous thrombosis. AcknowledgementsThis study was financially supported by a grant of the Dutch Cancer Foundation KWF/NKB UL-2006-3618. Disclosure of Conflict of InterestsThe authors state that they have no conflict of interest.

Interplay between alternatively spliced Tissue Factor and full length Tissue Factor in modulating coagulant activity of endothelial cells

“…Western blot analysis on MVs and supernatants revealed that asTF is not secreted from non-activated endothelial cells (data not shown). Also, stimulation of HUVEC cells with IL-1α did not result in asTF secretion, as previously reported by Böing et al [18]. However, other studies that utilized endothelial or malignant cell lines were able to demonstrate asTF in conditioned media and/or plasma of cancer patients [14,29].…”

“…Even though asTF promotes cancer progression non-proteolytically, coagulant properties of asTF and thus its involvement in thrombosis and/or hemostasis are controversial [18–20]. Both flTF and asTF accumulate in occlusive thrombi [21], suggesting a role for asTF in thrombus formation.…”

“…Another study showed that coagulant activity in supernatants from cytokine-stimulated endothelial cells decreased upon asTF depletion [20], but again this study did not explore whether asTF and flTF may synergize, or alternatively, have opposing functions in coagulation initiation. Finally, a study by Böing and colleagues found that asTF expressed in flTF-null HEK293 cells did not influence coagulation initiation, but again, this study did not evaluate the possible effects of asTF on flTF function [18]. …”

New Fundamentals in Hemostasis

“…Although the level of asTF in human plasma may be substantial, amounting to 10 -30% of total TF (107), the question of whether it contributes to coagulation is a matter of debate. Several observations suggest that asTF has a role in hemostasis: 1) asTF localizes on platelet surfaces in experimental blood clots; 2) the 165-166 lysine doublet involved in FVIIa binding is maintained in asTF, and theoretically, activity of the TF/FVIIa complex is maintained; 3) when added to plasma in vitro, asTF shortens the clotting time (31); and 4) while cell-expressed asTF alone does not appear to have procoagulant properties (32,47), endothelial asTF expression in the presence of TF may be procoagulant, as depletion of asTF reduced TFdependent coagulant activity (285). Thus asTF and flTF may cooperate in a synergistic fashion (FIGURE 2D), but such a mechanism, as well as how asTF would enhance function of normally spliced TF, remains speculative.…”

Alternatively Spliced Tissue Factor Is Not Sufficient for Embryonic Development

“…It is controversial whether asTF exhibits procoagulant activity [1], [3], [4], [5]. Although asTF lacks important residues that in flTF interact with macromolecular substrate, the majority of residues interacting with FVII(a) are present in flTF and asTF [6].…”