Tissue factor in thrombosis and hemorrhage (original) (raw)

The role of tissue factor in thrombosis and hemostasis

Physiol Res, 2007

The tissue factor (TF) is one of the most important regulators of arterial thrombosis. Because arterial thrombosis is the pathophysiologic background of acute coronary syndrome, the possible impact of blocking the arterial thrombosis on its onset is a challenging problem. The investigations of TF brought a new concept of "cell-based coagulation model" which highlighted the question of blood-borne TF as a source of TF in circulating blood. In this review we summarize essential information on the pathophysiology, molecular structure, expression and distribution of TF and we propose a novel concept of blood-borne TF, suggesting the possibilities of inhibition of the coagulation cascade with newly synthetized drugs.

Remodeling the Blood Coagulation Cascade

Journal of Thrombosis and Thrombolysis, 2000

The concept of a coagulation cascade describes the biochemical interactions of the coagulation factors, but has flaws as a model of the hemostatic process in vivo. For example, the model cannot explain why hemophiliacs bleed when they have an intact factor VIIa/tissue factor ("extrinsic") pathway. Hemostasis requires the formation of an impermeable platelet and fibrin plug at the site of vessel injury, but it also requires that the powerful procoagulant substances activated in this process remain localized to the site of injury.

Blood coagulation dynamics in haemostasis

Hämostaseologie, 2009

Our studies involve computational simulations, a reconstructed plasma/platelet proteome, whole blood in vitro and blood exuding from microvascular wounds. All studies indicate that in normal haemostasis, the binding of tissue factor (TF) with plasma factor (F) VIIa (extrinsic FXase complex) results in the initiation phase of the procoagulant response. This phase is negatively regulated by tissue factor pathway inhibitor (TFPI) in combination with antithrombin (AT) and the protein C (PC) pathway. The synergy between these inhibitors provides a threshold-limited reaction in which a stimulus of sufficient magnitude must be provided for continuation of the reaction. With sufficient stimulus, the FXa produced activates some prothrombin. This initial thrombin activates the procofactors and platelets required for presentation of the intrinsic FXase (FVIIIa-FIXa) and prothrombinase (FVa-FXa) complexes which drive the subsequent propagation phase; continuous downregulation of which is provid...

The Tissue Factor Requirement in Blood Coagulation

Journal of Biological Chemistry, 2005

Formation of thrombin is triggered when membrane-localized tissue factor (TF) is exposed to blood. In closed models of this process, thrombin formation displays an initiation phase (low rates of thrombin production cause platelet activation and fibrinogen clotting), a propagation phase (>95% of thrombin production occurs) and a termination phase (prothrombin activation ceases and free thrombin is inactivated). A current controversy centers on whether the TF stimulus requires supplementation from a circulating pool of blood TF in order to sustain an adequate procoagulant response. We have evaluated the requirement for TF during the progress of the blood coagulation reaction and have extended these analyses to assess the requirement for TF during resupply ("flow replacement"). Elimination of TF activity at various times during the initiation phase indicated: a period of absolute dependence (<10s); a transitional period in which the dependence on TF is partial and decreases as the reaction proceeds (10-240s); and a period in which the progress of the reaction is TF independent (>240s). Resupply of reactions late during the termination phase with fresh reactants, but no TF, yielded immediate bursts of thrombin formation similar in magnitude to the original propagation phases. Our data show that independence from the initial TF stimulus is achieved by the onset of the propagation phase and that the ensemble of coagulation products and intermediates which yield this TF independence maintain their prothrombin-activating potential for considerable time. These observations support the hypothesis that the transient, localized expression of TF is sufficient to sustain a TF-independent procoagulant response as long as flow persists.

The plasma hemostatic proteome: thrombin generation in healthy individuals

Journal of Thrombosis and Haemostasis, 2005

The range of plasma concentrations of hemostatic analytes in the population is wide. In this study these components of blood coagulation phenotype are integrated in an attempt to predict clinical risk. We modeled tissue factor (TF)-induced thrombin generation in the control population (N = 473) from the Leiden Thrombophilia Study utilizing a numerical simulation model. Hypothetical thrombin generation curves were established by modeling pro- and anticoagulant factor levels for each individual. These curves were evaluated using parameters which describe the initiation, propagation and termination phases of thrombin generation, i.e. time to 10 nm thrombin (approximate clot time), total thrombin and the maximum rates and levels of thrombin generated. The time to 10 nm thrombin varied over a 3-fold range (2.9-9.5 min), maximum levels varied over a approximately 4-fold range (200-800 nm), maximum rates varied approximately 4.8-fold (90-435 nm min(-1)) and total thrombin varied approximately 4.5-fold (39-177 microm s(-1)) within this control population. Thrombin generation curves, defined by the clotting factor concentrations, were distinguished by sex, age, alcohol consumption, body mass index (BMI) and oral contraceptive (OC) use (OC &gt; sex &gt; BMI &gt; age). Our results show that the capacity for thrombin generation in response to a TF challenge may represent a method to identify an individual&#39;s propensity for developing thrombosis.

Butenas et al Tissue Factor in Coagulation : Which ? Where ? When ? 1991

2009

Tissue factor (TF) is an integral membrane protein, normally separated from the blood by the vascular endothelium, which plays a key role in the initiation of blood coagulation. With a perforating vascular injury, TF becomes exposed to blood and binds plasma factor VIIa. The resulting complex initiates a series of enzymatic reactions leading to clot formation and vascular sealing. In some pathological states, circulating blood cells express TF as a result of exposure to an inflammatory stimulus leading to intravascular clotting, vessel occlusion, and thrombotic pathology. Numerous controversies have arisen related to the influence of structural features of TF, its presentation, and its function. There are contradictory reports about the synthesis and presentation of TF on blood cells and the presence (or absence) of functionally active TF circulating in normal blood either on microparticles or as a soluble protein. In this review we discuss TF structure-function relationships and th...

Thrombin functions during tissue factor-induced blood coagulation

Blood, 2002

Tissue factor-induced blood coagulation was studied in 20 individuals, for varying periods of time during 54 months, in contact pathway-inhibited whole blood at 37 degrees C and evaluated in terms of the activation of various substrates. After quenching over time with inhibitors, the soluble phases were analyzed for thrombin-antithrombin III (TAT) complex formation, prothrombin fragments, platelet activation (osteonectin release), factor Va generation, fibrinopeptide (FP) A and FPB release, and factor XIII activation. TAT complex formation, for 35 experiments, showed an initiation phase (up to 4.6 +/- 0.6 minutes) in which thrombin was generated at an average rate of 0.93 +/- 0.3 nM/min catalyzed by about 1.3 pM prothrombinase yielding approximately 26 nM thrombin. During a subsequent propagation phase, thrombin was generated at a rate of 83.9 +/- 3.8 nM/min by about 120 pM prothrombinase, reaching ultimate levels of 851 +/- 53 nM. Clot time, determined subjectively, occurred at 4.7 +/- 0.2 minutes and correlated with the inception of the propagation phase. The thrombin concentrations associated with the transitions to rapid product formation are 510 +/- 180 pM for platelet activation (1.9 +/- 0.2 minutes), 840 +/- 280 pM for factor XIII activation and factor Va generation (2.2 +/- 0.6 minutes), 1.3 +/- 0.4 nM for FPA release (2.5 +/- 0.7 minutes), 1.7 +/- 0.5 nM for FPB release and prethrombin 2 (2.8 +/- 0.8 minutes), 7.0 +/- 2.2 nM for thrombin B chain (3.6 +/- 0.2 minutes), and 26 +/- 6.2 nM for the propagation phase of TAT formation (4.6 +/- 0.6 minutes). These results illustrate that the initial activation of thrombin substrates occurs during the initiation phase at less than 2 nM thrombin (0.2%). Most thrombin (96%) is formed well after clotting occurs.

Tissue Factor in Coagulation: Which? Where? When? Arterioscler Thromb Vasc Biol

2009

Tissue factor (TF) is an integral membrane protein, normally separated from the blood by the vascular endothelium, which plays a key role in the initiation of blood coagulation. With a perforating vascular injury, TF becomes exposed to blood and binds plasma factor VIIa. The resulting complex initiates a series of enzymatic reactions leading to clot formation and vascular sealing. In some pathologic states, circulating blood cells express TF as a result of exposure to an inflammatory stimulus leading to intravascular clotting, vessel occlusion and thrombotic pathology. Numerous controversies have arisen related to the influence of structural features of TF, its presentation and its function. There are contradictory reports about the synthesis and presentation of TF on blood cells and the presence (or absence) of functionally active TF circulating in normal blood either on microparticles or as a soluble protein. In this review we discuss TF structure-function relationships and the ro...