Reversal of the inhibitory effect of Fondaparinux on Thrombin generation by rFVIIa, aCCP and PCC

Desmurs‐Clavel, H.; Huchon, Chantal; Chatard, B.; Négrier, Claude; Dargaud, Yesim

doi:10.1016/j.thromres.2008.07.007

Cited by 55 publications

(39 citation statements)

References 16 publications

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“…The activated PCC, FEIBA, was originally developed for hemophilia type A patients with high-titer inhibitors. Activated PCCs have also been studied in limited situations to reverse anticoagulants (12). The dose of either of the three classes of PCC noted to be effective in reversing the effects of warfarin or anti-factor Xa antagonists typically ranges from 20 to 50 U/kg, which is lower than that used to control bleeding in hemophiliacs (10).…”

Section: Discussionmentioning

confidence: 99%

Reversing Dabigatran in Life-Threatening Bleeding Occurring During Cardiac Ablation With Factor Eight Inhibitor Bypassing Activity

Dager¹,

Gosselin

Roberts³

2013

Critical Care Medicine

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Section: Discussionmentioning

confidence: 99%

Reversing Dabigatran in Life-Threatening Bleeding Occurring During Cardiac Ablation With Factor Eight Inhibitor Bypassing Activity

Dager¹,

Gosselin

Roberts³

2013

Critical Care Medicine

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Section: Discussionmentioning

confidence: 99%

“…Moreover, this plasmabased fluorogenic TG assay has been used to monitor rFVIIa activity in clinical settings 6 and laboratory investigations. 24,33 Although clot time is often used as the response measurement, we opted to use thrombin response in the present study because we found that clot time was a less-sensitive measure at high TF concentrations.Using the thrombin peak height readout, we demonstrated the existence of zymogen inhibition of the TF-dependent action of rFVIIa. rFVIIa in the absence of FVII zymogen expressed both TF-dependent and phospholipid-dependent (TF-independent) activities, but the addition of FVII delayed the onset and decreased TG induced by rFVIIa only in the presence of TF.…”

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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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“…Based on TEG, they found that rFVIIa exerted similar reversal effects on anticoagulated patient samples as on ex vivo samples and concluded that rFVIIa should be considered for patients with massive bleeding associated with these anticoagulants, which included fondaparinux. A more recent French study performed in vitro on blood from six healthy subjects showed that rFVIIa can only partially reverse the inhibitory effect of fondaparinux on thrombin generation 6. Again, both these studies are not in vivo studies, hence the clinical utility of use of rFVIIa in fondaparinux related bleeding is uncertain.…”

Section: Discussionmentioning

confidence: 99%

Life threatening retroperitoneal haemorrhage due to therapeutic fondaparinux

Pai

Payne²

2009

Case Reports

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We report the case of a patient with pulmonary embolism, treated with fondaparinux as bridging therapy until therapeutic levels were achieved on warfarin, who developed a non-traumatic massive retroperitoneal haematoma requiring substantial resuscitation with blood products and arterial embolisation. To our knowledge, this condition has not been reported with therapeutic doses of fondaparinux. Our patient, however, may have been more predisposed to bleeding due to the unpredictable pharmacokinetics of fondaparinux secondary to his morbid obesity, reduced clearance of the drug due to renal insufficiency and concomitant treatment with low dose aspirin and warfarin. Another consideration was the lack of a specific reversing agent for fondaparinux in the setting of a life threatening haemorrhage.

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Reversal of the inhibitory effect of Fondaparinux on Thrombin generation by rFVIIa, aCCP and PCC

Cited by 55 publications

References 16 publications

Reversing Dabigatran in Life-Threatening Bleeding Occurring During Cardiac Ablation With Factor Eight Inhibitor Bypassing Activity

Reversing Dabigatran in Life-Threatening Bleeding Occurring During Cardiac Ablation With Factor Eight Inhibitor Bypassing Activity

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

Life threatening retroperitoneal haemorrhage due to therapeutic fondaparinux

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