Gla-domainless factor Xa: molecular bait to bypass a blocked tenase complex

Marlu, Raphaël; Polack, Benoı̂t

doi:10.3324/haematol.2011.055699

Cited by 9 publications

(10 citation statements)

References 29 publications

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“…13 Thrombin generation induced by S195A GD-FXa on factor VIII-deficient plasma showed a dose-dependent effect (Figure 2) that was comparable to that of previously studied plasma-derived GD-FXa. 6 The same result was found in FIX immuno-depleted plasma. In addition, we tested plasmas from 4 severe hemophilia A patients and 4 severe hemophilia B patients.…”

Section: 7supporting

confidence: 74%

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Catalytically inactive Gla-domainless factor Xa binds to TFPI and restores ex vivo coagulation in hemophilia plasma

Ersayin¹,

Thomas²,

Seyve³

et al. 2017

Haematologica

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Section: 7supporting

confidence: 74%

“…6 Production of GD-FXa as recombinant protein was not successful. In contrast, the catalytically inactive mutant was successfully produced and used as antidote to direct oral anticoagulants, 8 but the general view was that a functional active site was required for TFPI binding.…”

Section: 7mentioning

confidence: 99%

Catalytically inactive Gla-domainless factor Xa binds to TFPI and restores ex vivo coagulation in hemophilia plasma

Ersayin¹,

Thomas²,

Seyve³

et al. 2017

Haematologica

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“…The plasma half‐life of rFIXa was lengthy (~41 min) and dramatically longer than FXa and thrombin (~1 min) (Fig. ) . The short plasma half‐lives of the latter proteases reflect both their relative inhibition rates by antithrombin and the presence of alternative plasma inhibitors .…”

Section: Discussionmentioning

confidence: 99%

Selective disruption of heparin and antithrombin-mediated regulation of human factor IX

Westmark

Tanratana

Sheehan

2015

Journal of Thrombosis and Haemostasis

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To cite this article: Westmark PR, Tanratana P, Sheehan JP. Selective disruption of heparin and antithrombin-mediated regulation of human factor IX. J Thromb Haemost 2015; 13: 1053-63.Summary. Background: Interaction with antithrombin and heparin regulates distribution, activity, and clearance of factor IXa (FIXa). Hemophilia B prophylaxis targets plasma FIX levels > 1% but neglects extravascular FIX, which colocalizes with antithrombin-heparan sulfate. Objective: Combined mutagenesis of FIX was undertaken to selectively disrupt heparin-and antithrombin-mediated regulation of the protease. Methods: Human FIX alanine substitutions in the heparin (K126A and K132A) and antithrombin (R150A) exosites were characterized with regard to coagulant activity, plasma thrombin generation, antithrombin inhibition, and plasma half-life. Results: Single or combined (K126A/R150A or K132A/R150A) exosite mutations variably reduced coagulant activity relative to wild-type (WT) for FIX (27-91%) and FIXa (25-91%). Double mutation in the heparin exosite (K126A/K132A and K126A/K132A/R150A) markedly reduced coagulant activity (7-21%) and plasma TG. In contrast to coagulant activity, FIX K126A (1.8-fold), R150 (1.6-fold), and K132A/R150A (1.3-fold) supported increased tissue factor-initiated plasma TG, while FIX K132A and K126A/ R150A were similar to WT. FIXa K126A/R150A and K132A/R150A (1.5-fold) demonstrated significantly increased FIXa-initiated TG, while FIXa K132A, R150A, and K126A (0.8-0.9-fold) were similar to WT. Dual mutations in the heparin exosite or combined mutations in both exosites synergistically reduced the inhibition rate for antithrombin-heparin. The half-life of FIXa WT in FIX-deficient plasma was remarkably lengthy (40.9 AE 1.4 min) and further prolonged for FIXa R150A, K126A/ R150A, and K132A/R150A (> 2 h). Conclusion: Selective disruption of exosite-mediated regulation by heparin and antithrombin can be achieved with preserved or enhanced thrombin generation capacity. These proteins should demonstrate enhanced therapeutic efficacy for hemophilia B.

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“…51 The focus in this section will be on the thrombin generation assay. As illustrated in Figure 2, the addition of emicizumab, nanobodies against antithrombin, 52 or polyclonal antibodies against TFPI 53 has a strong stimulating effect on the thrombin generation profile in FVIII-deficient plasma. Thus, the presence of the procoagulant antibody emicizumab or the functional absence of antithrombin or TFPI results in increased thrombin peaks and the endogenous thrombin potential compared with FVIII-deficient plasma alone.…”

Section: Monitoring the Effect Of Nonfactor Therapies On The Hemostatmentioning

confidence: 99%

“…52 (C) Tissue factor-induced thrombin generation in the absence or presence of polyclonal anti-TFPI antibodies. 53 FVIII. The animals then received either emicizumab to a concentration of 6 mg/mL or porcine FVIII (which is not recognized by the anti-FVIII antibody) to a concentration of 0.01 U/mL (1%).…”

Section: Monitoring the Fviii Equivalence Of Nonfactor Therapiesmentioning

confidence: 99%

Laboratory monitoring of hemophilia A treatments: new challenges

Lenting

2020

Blood Advances

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Monitoring factor VIII (FVIII) activity has traditionally been complicated by discrepancies between assays for the various sorts of FVIII molecules. The advent of novel nonfactor therapies (emicizumab, fitusiran, and anti-tissue factor pathway inhibitor antibodies) in hemophilia A poses a new level of difficulty on the laboratory monitoring of these patients. To use the correct assays and for a proper interpretation of their results, it is pertinent to understand the mode of action of these nonfactor agents. Furthermore, the biochemical consequences for the different types of activity assays (whether it be specific FVIII activity assays or global coagulation assays) should be taken into account as well. In this review, these aspects will be discussed. In addition, the use of various animal models to estimate FVIII-equivalence of the nonfactor therapies will be presented.

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Gla-domainless factor Xa: molecular bait to bypass a blocked tenase complex

Cited by 9 publications

References 29 publications

Catalytically inactive Gla-domainless factor Xa binds to TFPI and restores ex vivo coagulation in hemophilia plasma

Catalytically inactive Gla-domainless factor Xa binds to TFPI and restores ex vivo coagulation in hemophilia plasma

Selective disruption of heparin and antithrombin-mediated regulation of human factor IX

Laboratory monitoring of hemophilia A treatments: new challenges

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