Extrinsic Activation of Human Blood Coagulation Factors IX and X

Bom, Vjj; Reinalda-Poot, J; Cupers, R; Bertina, R. M.

doi:10.1055/s-0038-1645199

Cited by 16 publications

(13 citation statements)

References 24 publications

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“…Vm (Vmax) and Km values were calculated from Woolf plots as in Figs. 4 rophages (258 nM), but very similar to that obtained in a cell-free system (35,41,49). The Km of factor IX was 1.1-2.3-fold higher than the Km of factor X, whereas the Vmax of factor IX activation was 3-fold lower than that of factor X activation.…”

Section: Kinetic Parameters Of Extrinsic Activation Of Factor X and Fsupporting

confidence: 78%

“…Data for the cell-free system are taken from ref. 35; these reactions were performed at 0.4-0.6 nM tissue factor apoprotein, 25 µM phospholipid (50 mol% phosphatidylserine: 50 mol% phosphatidylcholine) and 0.01 nM factor Vila. Vm (Vmax) and Km values were calculated from Woolf plots as in Figs.…”

Section: Kinetic Parameters Of Extrinsic Activation Of Factor X and Fmentioning

confidence: 99%

“…In this study we investigated the activation of purified fac tors IX and X by factor Vila and factor VII on the surface of endotoxin-stimulated human umbilical vein endothelial cells. We determined the kinetic parameters for the activation of both factor X and factor IX which were compared with those obtained in previous studies with purified human tissue factor apoprotein reconstituted with phospholipids (34,35). The results show that the catalytic efficiency (Kcat/Km) of the extrinsic activation of factor IX -when compared to that of factor X -is 5-fold lower on the cellular surface than on the purified phospholipid surface due to a more unfavourable Km of factor IX.…”

Section: Introductionmentioning

confidence: 97%

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Extrinsic Activation of Human Coagulation Factors IX and X on the Endothelial Surface

Bom¹,

Hinsbergh²,

Reinalda-Poot³

et al. 1991

Thromb Haemost

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SummaryIn previous kinetic studies, the catalytic efficiency of the activation of human coagulation factors IX and X by factor VIIa in the presence of purified tissue factor apoprotein was found to be essentially equal. These activation reactions were now studied on the surface of human umbilical vein endothelial cells. The cells were stimulated with endotoxin to express tissue factor. This tissue factor activity was saturable with factor VIIa and could be inhibited by rabbit antibodies against human tissue factor apoprotein. Only stimulated cells supported factor VIIa activity. No difference in the reactivity of factor VII and VIIa was observed in the presence of factor X, due to rapid feedback activation of factor VII by factor Xa. However, the activation of factor IX by factor VII shows a 10 min lag-phase, which reflects that the activation of factor VII by factor IXa is a less efficient process. The kinetic parameters for the factor VIIa dependent activation of factor IX and factor X on the endothelial surface were: Km 0.09 εM, Vmax 0.13 pmol/min, and Km 0.071 εM, Vmax 0.41 pmol/min, respectively. The same ratio between the Vmax for factor X and factor IX activation was observed as in a cell free system. However, the Km of factor IX was 4-fold higher on the endothelial surface than in the cell free system. Together, these kinetic parameters will favour factor X activation 5-fold over factor IX activation at physiological concentrations of these proteins.The activation of factor X by factor VIIa on the endothelial surface was characterized by a short lag-phase, which was absent in factor IX activation. Further, both the activation of factor X and factor IX were down regulated by factor Xa.

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Section: Kinetic Parameters Of Extrinsic Activation Of Factor X and Fsupporting

confidence: 78%

Section: Kinetic Parameters Of Extrinsic Activation Of Factor X and Fmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

See 1 more Smart Citation

Extrinsic Activation of Human Coagulation Factors IX and X on the Endothelial Surface

Bom¹,

Hinsbergh²,

Reinalda-Poot³

et al. 1991

Thromb Haemost

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“…This leads to the conclusion that additional VKDP at elevated concentrations have pronounced inhibitory effect on thrombin generation. Data published from several laboratories have established that FIX inhibits FX activation by the FVIIa/TF complex due to the competition of these two zymogens for the same complex enzyme [23,38–42]. In this study a substantial increase in the duration of the initiation phase was observed when an elevated concentration of FIX was present in a reaction with phospholipids in the absence of FXI.…”

Section: Discussionmentioning

confidence: 55%

The function of factor XI in tissue factor-initiated thrombin generation

Butenas

Dee

Mann

2003

Journal of Thrombosis and Haemostasis

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To cite this article: Butenas S, Dee JD, Mann KG. The function of factor XI in tissue factor-initiated thrombin generation. J Thromb Haemost 2003;See also Walsh PN. Roles of Factor XI, platelets and tissue factor-initiated blood coagulation. This issue, pp. 2081±6.Summary. The in¯uence of plasma and platelet factor (F)XI on thrombin generation initiated with 10 pM tissue factor (TF) in a synthetic coagulation model was evaluated in the presence of either 2 Â 10 8 mL À1 platelets or the equivalent (2 mM) phospholipids. In either system, with all proteins present at physiological concentrations, FXI (30 nM) had no effect on thrombin generation. With phospholipids in the absence of FXI, an increase in vitamin K-dependent proteins (VKDP) (up to 500%) signi®-cantly prolonged the initiation phase of thrombin generation and decreased maximum thrombin levels. The inhibition was principally caused by the elevated prothrombin and FIX concentrations. When 30 nM FXI was added with elevated VKDP and phospholipids, the initiation phase was decreased and the maximum thrombin levels generated substantially increased. In experiments with platelets (with and without plasma FXI), an increase in VKDP had little effect on the initiation phase of thrombin generation. These data indicate that (i) FXI has no effect on thrombin generation at 10 pM TF and physiological concentrations of VKDP; (ii) platelets and plasma FXI are able to compensate for the inhibitory effects of elevated VKDP.

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“…As in the experimental system (15), the TF-VIIa complex is assumed to be fully formed at the start of the experiment, so descriptions of the binding of VII(a) to TF and the activation of VII are not included. The TF-VIIa complex activates both IX (17) and X (18). IXa forms complexes with VIII (19) or VIIIa (20); the VIIIa-IXa (tenase) complex also activates X (21,22).…”

Section: Resultsmentioning

confidence: 99%

Mathematical Model of Serine Protease Inhibition in the Tissue Factor Pathway to Thrombin

Leipold

Bozarth

Racanelli

et al. 1995

Journal of Biological Chemistry

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A mathematical model has been developed to simulate the generation of thrombin by the tissue factor pathway. The model gives reasonable predictions of published experimental results without the adjustment of any parameter values. The model also accounts explicitly for the effects of serine protease inhibitors on thrombin generation. Simulations to define the optimum affinity profile of an inhibitor in this system indicate that for an inhibitor simultaneously potent against VIIa, IXa, and Xa, inhibition of thrombin generation decreases dramatically as the affinity for thrombin increases. Additional simulations show that the reason for this behavior is the sequestration of the inhibitor by small amounts of thrombin generated early in the reaction. This model is also useful for predicting the potency of compounds that inhibit thrombosis in rats. We believe that this is the first mathematical model of blood coagulation that considers the effects of exogenous inhibitors. Such a model, or extensions thereof, should be useful for evaluating targets for therapeutic intervention in the processes of blood coagulation.The clotting of blood is an exquisitely complex process. The simultaneous requirements for the free flow of blood under normal conditions and rapid clotting to prevent blood loss in the case of injury require a delicate balance between clot formation and clot lysis. Taken together, these processes involve more than 30 proteins, at least 10 of which are serine proteases. Inhibitors of serine proteases occur as natural anticoagulants, and natural and synthetic inhibitors have been widely studied for therapeutic applications in the prevention of thrombosis (1).When choosing candidate serine protease inhibitors for therapeutic use, the choice of a target enzyme may be less than obvious. Many of the enzymes have multiple activities, there is positive and negative feedback regulation, and there are alternative pathways for activation and inactivation. In addition, serine protease inhibitors (especially synthetic compounds) generally have a spectrum of activities due to the high degrees of homology among the blood coagulation factors. This raises the question of whether the best antithrombotic compound would be specific for a single enzyme or show affinities for several serine proteases (2).Mathematical modeling can help us understand such complex systems, but published models of blood coagulation suffer from the following limitations: consideration of only a small part of the coagulation cascade (3-7), empirical description of interactions for which molecular mechanisms were known (3, 8, 9), determination of some (4, 9, 10) or all (3, 11) of the parameter values from the experimental data to which the model predictions were then compared (curve fitting), and the absence of comparisons of model predictions to experimental data (6,(12)(13)(14). In the best of these studies (4, 5, 7), most or all of the parameter values were independently determined, model predictions were compared to experimental results that had not...

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Extrinsic Activation of Human Blood Coagulation Factors IX and X

Cited by 16 publications

References 24 publications

Extrinsic Activation of Human Coagulation Factors IX and X on the Endothelial Surface

Extrinsic Activation of Human Coagulation Factors IX and X on the Endothelial Surface

The function of factor XI in tissue factor-initiated thrombin generation

Mathematical Model of Serine Protease Inhibition in the Tissue Factor Pathway to Thrombin

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