Recombinant human factor VIIa (rFVIIa) cleared principally by antithrombin following intravenous administration in hemophilia patients

Agersø, Henrik; Brophy, Donald F.; Pelzer, H.; Martin, Erika J.; Carr, Marcus E.; Hedner, Ulla; Ezban, Mirella

doi:10.1111/j.1538-7836.2010.04152.x

Cited by 43 publications

(45 citation statements)

References 28 publications

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“…This was an extension of a previous pharmacokinetic/ pharmacodynamic study of rFVIIa 90 mg/kg in nonbleeding hemophiliacs [13,14]. The same patients from the previous study were enrolled in this study.…”

Section: Patients and Study Proceduresmentioning

confidence: 97%

“…Patients 4, 7, 8 and 9 were characterized as delayed laboratory responders to rFVIIa 90 mg/kg based upon the previous in-vivo study, whereas patients 1-3, 5, 6, and 10 had a rapid laboratory response during the prior in-vivo study [13,14]. Table 2 provides the clinical bleeding history of all participants, and those deemed delayed laboratory responders experienced 12-59 bleeds requiring from 37 to 118 infusions of on-demand treatment during 2009.…”

Section: Patient Characteristicsmentioning

confidence: 99%

“…Recently a pharmacokinetic/pharmacodynamic study of intravenous rFVIIa 90 mg/kg was conducted in 10 severe nonbleeding hemophilia patients (1 with a FVIII inhibitor; 9 without) [13,14]. Whole blood coagulation profiles were characterized over 6 h using thromboelastography (TEG), rotational thromboelastometry (ROTEM), and the Hemodyne Hemostasis Analysis System (HAS).…”

Section: Introductionmentioning

confidence: 99%

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Overcoming delayed in-vitro response to rFVIIa

Brophy

Martin²,

Barrett³

et al. 2011

Blood Coagulation &Amp; Fibrinolysis

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In a previous pharmacokinetic/pharmacodynamic study in nonbleeding hemophilia patients, variability in laboratory response to recombinant factor VIIa (rFVIIa) 90 μg/kg was noted, and the patients were described as delayed or rapid laboratory responders based on time to clot formation. The current study determined whether in-vitro experiments could reproduce previous in-vivo findings; whether the delayed laboratory response to rFVIIa 90 μg/kg is improved by spiking with high-dose rFVIIa or rFVIIa analogue (vatreptacog alfa); whether a dose-response is observed with our method. In-vitro experiments were conducted in our previous patient cohort using rFVIIa 1.28 and 3.84 μg/ml and vatreptacog alfa 0.28 and 0.56 μg/ml. Whole blood studies were conducted using the Hemodyne Hemostasis Analysis System (platelet contractile force, clot elastic modulus, force onset time) and rotational thromboelastometry (clotting time, maximum clot firmness). Spiking with rFVIIa 1.28 μg/ml showed the same distribution of delayed and rapid laboratory response as observed previously. Increasing in-vitro rFVIIa concentrations improved the coagulation parameters; however, there remained delayed and rapid responders. Vatreptacog alfa improved the coagulation parameters at all concentrations tested, and the 0.56 μg/ml concentration normalized the force onset time, platelet contractile force, clot elastic modulus and clotting time parameters. A dose-response was observed with both assays. There was good agreement between the laboratory responses obtained after intravenous administration of rFVIIa 90 μg/kg and in-vitro spiking studies. Escalating rFVIIa and vatreptacog alfa concentrations improved coagulation parameters in all patients compared to rFVIIa 1.28 μg/ml. Vatreptacog alfa produced more pronounced coagulation effects at lower concentrations than rFVIIa; and the 0.56 μg/ml concentration completely normalized responses in all patients.

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Section: Patients and Study Proceduresmentioning

confidence: 97%

Section: Patient Characteristicsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Overcoming delayed in-vitro response to rFVIIa

Brophy

Martin²,

Barrett³

et al. 2011

Blood Coagulation &Amp; Fibrinolysis

View full text Add to dashboard Cite

show abstract

“…Conversely, we speculate that increasing the dose along the range of saturation plateau is not wasteful because it may prolong the action of rFVIIa beyond the half-life of approximately 2.5 hours. 37,39 Increasing the dose in this manner would extend the drug's action without increasing the maximal hemostatic response and any potentially associated thrombogenic risk.…”

Section: Discussionmentioning

confidence: 99%

“…4,5,22 In our experiments, the inhibitory effects of FVII were observed below a 15nM concentration of rFVIIa, which lies within the concentration range of 10-25nM expected after injection of a 90 g/kg dose. 37 The existence of FVII-dependent inhibition of rFVIIa implies that the efficacy of the drug may depend on the amount of FVII in circulation because of the current dose acting in the TF-dependent range, but only if TF is exposed at low density. In the extreme cases of FVII-deficient patients, lower doses of rFVIIa 38 should prove to be effective.…”

Section: Discussionmentioning

confidence: 99%

Unifying the mechanism of recombinant FVIIa action: dose dependence is regulated differently by tissue factor and phospholipids

Shibeko

Woodle

Lee

et al. 2012

Blood

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Recombinant factor VIIa (rFVIIa) is used for treatment of hemophilia patients with inhibitors, as well for off-label treatment of severe bleeding in trauma and surgery. Effective bleeding control requires supraphysiological doses of rFVIIa, posing both high expense and uncertain thrombotic risk. Two major competing theories offer different explanations for the supraphysiological rFVIIa dosing requirement: (1) the need to overcome competition between FVIIa and FVII zymogen for tissue factor (TF) binding, and (2) a highdose-requiring phospholipid-related pathway of FVIIa action. In the present study, we found experimental conditions in which both mechanisms contribute simultaneously and independently to rFVIIa-driven thrombin generation in FVIIdeficient human plasma. From mathematical simulations of our model of FX activation, which were confirmed by thrombingeneration experiments, we conclude that the action of rFVIIa at pharmacologic doses is dominated by the TF-dependent pathway with a minor contribution from a phospholipid-dependent mechanism. We established a dose-response curve for rFVIIa that is useful to explain dosing strategies. In the present study, we present a pathway to reconcile the 2 major mechanisms of rFVIIa action, a necessary step to understanding future dose optimization and evaluation of new rFVIIa analogs currently under development. IntroductionThe use of a recombinant factor VIIa (rFVIIa) product, NovoSeven, which is licensed for the treatment of hemophilia patients with inhibitory Abs against factor VIII (FVIII) or factor IX (FIX), has proven to be safe and efficacious, but its dosing remains problematic. [1][2][3][4] The recommended dosing schedule is a supraphysiological dose of 90 g/kg every 2-3 hours until hemostasis is achieved, producing an approximately 250-fold increase above basal plasma concentrations of FVIIa (0.1 to 25nM). 5 Not only does such a treatment regimen incur a high cost, but ineffective drug responses and thrombotic complications have also been reported. [6][7][8][9] However, our current understanding of the mechanism of rFVIIa action is unclear, limiting our ability to optimize the safety and cost of treatment. 10,11 Off-label use of rFVIIa for nonhemophilia patients at similar high doses indicates that the high dose required for hemophilia treatment cannot be explained by deficiencies of FVIII or FIX alone. 5,12 FVIIa is a weak enzyme and its activity requires either of 2 cofactors, tissue factor (TF) or negatively charged phospholipids. 13 Disagreement over which of the 2 cofactors explains the high pharmacologic dose of the drug has led to TF-and phospholipiddependent theories of rFVIIa action. Although these mechanisms may appear to be nonexclusive, the 2 theories support opposing approaches to dose adjustment.The TF-dependent mechanism suggests that the hemostatic effect of rFVIIa is mediated by its binding to TF expressed on cell surfaces at the site of injury, 14 forming the extrinsic tenase complex, which activates factor X (FX), leading to thrombin genera...

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In vitro characterization of CT‐001—a short‐acting factor VIIa with enhanced prohemostatic activity

Sim

Mallari

Teare

et al. 2021

Research and Practice in Thrombosis and Haemostasis

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Background Traumatic injury and the associated acute bleeding are leading causes of death in people aged 1 to 44 years. Acute bleeding in pathological and surgical settings also represents a significant burden to the society. Yet there are no approved hemostatic drugs currently available. While clinically proven as an effective pro‐coagulant, activated factor VII (FVIIa) use in acute bleeding has been hampered by unwanted thromboembolic events. Enhancing the ability of FVIIa to quickly stop a bleed and clear rapidly from circulation may yield an ideal molecule suitable for use in patients with acute bleeding. Objectives To address this need and the current liability of FVIIa, we produced a novel FVIIa molecule (CT‐001) with enhanced potency and shortened plasma residence time by cell line engineering and FVIIa protein engineering for superior efficacy for acute bleeding and safety. Methods To address safety, CT‐001, a FVIIa protein with 4 desialylated N‐glycans was generated to promote active recognition and clearance via the asialoglycoprotein receptor. To enhance potency, the gamma‐carboxylated domain was modified with P10Q and K32E, which enhanced membrane binding. Results Together, these changes significantly enhanced potency and clearance while retaining the ability to interact with the key hemostatic checkpoint proteins antithrombin and tissue factor pathway inhibitor. Conclusions These results demonstrate that a FVIIa molecule engineered to combine supra‐physiological activity and shorter duration of action has the potential to overcome the current limitations of recombinant FVIIa to be a safe and effective approach to the treatment of acute bleeding.

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Recombinant human factor VIIa (rFVIIa) cleared principally by antithrombin following intravenous administration in hemophilia patients

Cited by 43 publications

References 28 publications

Overcoming delayed in-vitro response to rFVIIa

Overcoming delayed in-vitro response to rFVIIa

Unifying the mechanism of recombinant FVIIa action: dose dependence is regulated differently by tissue factor and phospholipids

In vitro characterization of CT‐001—a short‐acting factor VIIa with enhanced prohemostatic activity

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