Response: Mechanism of Action of High-Dose Factor VIIa

Mann, Kenneth G.; Butenas, Saulius

doi:10.1161/01.atv.0000047646.64969.8b

Cited by 7 publications

(5 citation statements)

References 11 publications

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“…22 Thus, a picture emerges in which the surface of collagen-treated platelets exert a dual role: (1) thrombin-activated platelets offer binding sites (GPIb ␣ ) for both factor XI and thrombin; and (2) collagen/ thrombin-activated platelets provide procoagulant anionic phospholipids that support the assembly of prothrombin and factor X converting enzyme complexes on platelet surfaces. That these phospholipids alone or in combination with protein receptors on the platelet surface mediate thrombin generation is consistent with the fact that a protein with high 24 The question has been addressed to what extent high-dose factor VIIa supports thrombin generation in a TF-independent manner. Our results confirm that supraphysiological factor VIIa concentrations increase dose-dependently thrombin generation only in the presence of platelets.…”

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confidence: 74%

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Factor XI–Dependent Reciprocal Thrombin Generation Consolidates Blood Coagulation when Tissue Factor Is Not Available

Wielders

Béguin

Hemker

et al. 2004

ATVB

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Objective-Feedback activation of factor XI by thrombin is a likely alternative for tissue factor-dependent propagation of thrombus formation. However, the hypothesis that thrombin can initiate and propagate its formation in a factor XI-dependent and platelet-dependent manner has not been tested in a plasma milieu. Methods and Results-We investigated thrombin generation in recalcified platelet-rich plasma activated with varying amounts of thrombin or factor VIIa. Thrombin initiates and propagates dose-dependently thrombin generation only when platelets and plasma factor XI are present. Incubation of thrombin-activated platelets with a tissue factor neutralizing antibody had no effect on thrombin formation, indicating that platelet-associated tissue factor, if present at all, is not involved. In the absence of factor VIII, thrombin could not initiate its own formation, whereas factor VIIa-induced thrombin generation was reduced. Collagen strongly stimulated both thrombin-initiated and factor VIIa-initiated thrombin generation. Conclusions-These findings support the notion that platelet-localized feedback activation of factor XI by thrombin plays an important role in maintaining normal hemostasis as well as in sustaining thrombus formation when the TF pathway is inhibited by tissue factor pathway inhibitor. Key Words: factor XI Ⅲ thrombin Ⅲ clot formation Ⅲ activated platelets Ⅲ factor VIIa Ⅲ collagen I t is generally appreciated that thrombin-mediated feedback activation of factor XI contributes to the consolidation phase of clot formation. [1][2][3] In this process, thrombin that is initially generated via the tissue factor (TF) pathway, activates factor XI on the surface of (thrombin-activated) activated platelets. 4 The accelerating role of activated platelets in thrombin-catalyzed factor XI activation is thought to result from the colocalization of thrombin and factor XI on the platelet membrane glycoprotein (GP) Ib␣ within the GP Ib-IX-V complex. 5,6 Thrombin-activated factor XI, therefore, could be critical to the propagation of thrombin generation once the TF pathway is inhibited by TF pathway inhibitor (TFPI).Hypothetically, thrombin-catalyzed factor XI activation could play a major role in the development of growing thrombi. Besides circulating cell-bound TF, the continuous supply of factor XI by blood flow to a thrombin-containing thrombus surface might result in a factor XIa-driven thrombin production that in turn will accelerate the rate of thrombus growth. 7 An additional argument for an important contribution of a factor XI-dependent thrombus growth is found in the observation that factor XI activation seems to be confined to the surface of an activated platelet. 8 The latter optimizes the thrombin generating potency because of maintaining high local concentrations of reactants and the inability to be inactivated by plasma protease inhibitors.The present work was undertaken to explore the role of thrombin in initiating its own production by feedback activation of factor XI under physiological conditi...

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confidence: 74%

“…23,24 The question has been addressed to what extent high-dose factor VIIa supports thrombin generation in a TF-independent manner. Our results confirm that supraphysiological factor VIIa concentrations increase dose-dependently thrombin generation only in the presence of platelets.…”

Section: Discussionmentioning

confidence: 99%

Factor XI–Dependent Reciprocal Thrombin Generation Consolidates Blood Coagulation when Tissue Factor Is Not Available

Wielders

Béguin

Hemker

et al. 2004

ATVB

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“…High doses of recombinant FVIIa (rFVIIa) have been found to bypass FIX or FVIII deficiency and ameliorate the bleeding problems associated with hemophilic patients with inhibitors [4,5]. Although the precise mechanism of FVIIa action in patients with hemophilia is still a matter of debate [6,7], it is believed that FVIIa, at pharmacologic doses, binds to activated platelets and subsequently generates a thrombin burst via activation of FX in a TF-independent manner [8]. However, the effectiveness of FVIIa to restore the hemostasis fully in hemophilia may depend on the presence of TF at the site of vascular lesion [9,10].…”

Section: Introductionmentioning

confidence: 99%

Activity and Regulation of Factor VIIa Analogs with Increased Potency at the Endothelial Cell Surface.

Ghosh

Ezban

Persson

et al. 2006

Blood

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To cite this article: Ghosh S, Ezban M, Persson E, Pendurthi U, Hedner U, Rao LVM. Activity and regulation of factor VIIa analogs with increased potency at the endothelial cell surface. J Thromb Haemost 2007; 5: 336-46. Summary. Background: Variants of recombinant factor VIIa (rFVIIa) with increased intrinsic activity have been developed to improve efficacy in the treatment of bleeding disorders in the future. The increased potency of FVIIa variants was demonstrated in limited in vitro and in vivo studies. However, further characterization of FVIIa variants is needed to evaluate their potential clinical use. Methods: In the present study, we investigated the interactions of two FVIIa variants, FVIIa Q and FVIIa DVQ , with plasma inhibitors, tissue factor pathway inhibitor (TFPI) and antithrombin (AT), and vascular endothelium. TF-FVIIa activity or its inhibition was measured directly in an amidolytic activity assay or for its ability to activate factor X. Results: Both TFPI and AT/heparin inhibited the FVIIa variants more rapidly than the wild-type (WT) FVIIa in the absence of tissue factor (TF). In the presence of TF, TFPI, TFPI-Xa, and AT/heparin inhibited FVIIa and FVIIa variants at similar rates. Although the WT FVIIa failed to generate significant amounts of FXa on unperturbed endothelial cells, FVIIa variants, particularly FVIIa DVQ , generated a substantial amount of FXa on unperturbed endothelium. Annexin V fully attenuated the FVIIa-mediated activation of FX on unperturbed endothelial cells. On stimulated human umbilical vein endothelial cells, FVIIa and FVIIa variants activated FX at similar rates, and annexin V blocked the activation only partly. AT/heparin and TFPI-Xa inhibited the activity of FVIIa and FVIIa variants bound to endothelial cell TF in a similar fashion. Interestingly, despite significant differences observed in FXa generation on unperturbed endothelium exposed to FVIIa and FVIIa analogs, no differences were found in thrombin generation when cells were exposed to FVIIa or FVIIa analogs under plasma mimicking conditions. Conclusion: Overall, the present data suggest that although FVIIa variants generate substantial amounts of FXa, they do not generate excessive thrombin on the surface of endothelium.

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“…Also, TF‐independent thrombin generation by rFVIIa on platelets adhered to a collagen surface under flow conditions was demonstrated by our laboratory [12]. Discrepancies between these studies and the studies from Butenas and coworkers have been attributed to differences in the TF source [13,14]. Also in the present article it is described that TF‐independent thrombin generation does not occur in the presence of pharmacological rFVIIa concentrations, even when a high concentration of preactivated platelets are added to either model system described.…”

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confidence: 99%