Influence of Factor VIIa and Phospholipids on Coagulation in “Acquired” Hemophilia

Butenas, Saulius; Brummel, Kathleen E.; Paradis, Sara G.; Mann, Kenneth G.

doi:10.1161/01.atv.0000042081.57854.a2

Cited by 58 publications

(66 citation statements)

References 37 publications

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“…The available doses of FVIIa-PCPS did not seem to alter either hemostatic function or BT in these limited trials, despite the fact that such concentrations were effective in enhancing coagulation function in vitro [29]. These doses of FVIIa, however, were much lower than those previously shown to be efficacious for recombinant FViIa in swine [23].…”

Section: Discussionmentioning

confidence: 77%

“…Table 3. Administration of FVHa with PCPS at concentrations previously found to be efficacious in in vitro studies [29] did not seem to decrease BT or enhance coagulation function in these three animals. Furthermore, administration of FVIIa-PCPS did not produce alterations in MAP.…”

mentioning

confidence: 62%

“…As these were preliminary screening experiments, a variety of doses were used (Table 1). Doses were chosen based on previous in vitro [29] and in vivo [31][32][33] experiments and in consultation with Dr. Nesheim. In each experiment, the initial infusion of drug consisted of an identical volume of LR (at TI) to serve as control; all T I values reported in the tables that follow are therefore baseline levels.…”

Section: Injury Phasementioning

confidence: 99%

“…Butenas and his colleagues have recently demonstrated the influence of rVIIa and PCPS lipid vesicles on thrombin generation and clot formation in vitro [29,30].…”

Section: Introductionmentioning

confidence: 99%

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Testing of Intravenous Hemostatic Agents in a Novel Swine Model of Bleeding: Preliminary Results With FXa-PCPs

Ryan¹,

Dorfman²,

Jenny³

et al. 2005

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The public reporting burden for this collection of information is estimated to average 1 hour por reaponse. including the time for reviewing instructions. aearching existing data sources, gatharin9 and maintaining the data needed. and completing and reviewing the collection of Information. Send comments regarding this burden estimate or any other aspect of thia collection of information, including suggestions for reducing the burden, to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reaports 10704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Rleapondenta should be aware that notwithstanding any other proviaion of law, no person shall be subject to any penalty for failing to comply with a collection of information if it doea not diaplay a currently valid 0M8 control number. PLEASE DO NOT RETURN YOUR PERFORMING ORGANIZATION NAME(S) AND ADORESSDESS). PERFORMING ORGANIZATION SPONSORING/MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITORS ACRONYM(S)U ABSTRACTFinding an intravenous treatment that could assist endogenous clotting mechanisms is a major mission for military researchers. Herein, we report preliminary data on the efficacy of mixtures of highly purified blood coagulation factors (FVIIa and FXa) and phospholipids vesicles (PCPS) to reduce traumatic bleeding. A novel swine model was developed in which 1) bleeding times (BT) and coagulation function could be ascertained following multiple doses of drug administration; and, 2) an exsanguinating injury could subsequently be performed in the same animal, yielding screening information as to the effects of drug pretreatment of blood loss and survival. FXa-PCPS failed to reduce BT or enhance coagulation function and a dose-dependent hypotensive response. FVIIa-PCPS yielded no data suggestive of the profound potentiation of FVIIa activity by PCPS observed in previous in vitro testing.Further study of these drugs for the use of traumatic hemorrhage is not warranted. SUBJECT TERMS

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Section: Discussionmentioning

confidence: 77%

mentioning

confidence: 62%

Section: Injury Phasementioning

confidence: 99%

“…Butenas and his colleagues have recently demonstrated the influence of rVIIa and PCPS lipid vesicles on thrombin generation and clot formation in vitro [29,30].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Testing of Intravenous Hemostatic Agents in a Novel Swine Model of Bleeding: Preliminary Results With FXa-PCPs

Ryan¹,

Dorfman²,

Jenny³

et al. 2005

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“…19,34 Indeed, procoagulant phospholipids provided by platelets, 22,35 platelet microparticles, 24,35 or synthetic vesicles 20,24 promoted rFVIIa action. In the absence of TF, only doses above 50nM rFVIIa were able to generate phospholipid-dependent TG in our model.…”

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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Synthesis and characterization of recombinant factor VIIa‐conjugated magnetic iron oxide nanoparticles for hemophilia treatment

Shafir

Galperin

Margel

2008

J Biomedical Materials Res

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Maghemite (gamma-Fe(2)O(3)) nanoparticles of 15.0 +/- 2.1 nm in diameter were prepared by nucleation, followed by controlled growth of magnetic iron oxide thin films onto gelatin nuclei. Functionalization of these magnetic nanoparticles with activated double bonds was accomplished by interacting divinyl sulfone with the gelatin coating of the gamma-Fe(2)O(3) nanoparticles. The activated double bonds were then used for covalent binding, via Michael addition reaction, of recombinant factor VIIa and human serum albumin to the surface of these nanoparticles. Recombinant factor VIIa was also physically bound to the magnetic nanoparticles by interacting this factor with the human serum albumin conjugated gamma-Fe(2)O(3) nanoparticles. The influence of factor VIIa concentration on the immobilization yield has been elucidated. Leakage of the bound factor VIIa into PBS containing 4% albumin was insignificant. The coagulant activity of the physically adsorbed recombinant factor VIIa was similar to that of the free one and was significantly better than that of the covalently bound. The blood half-life of free factor VIIa is short, about 2-3 h, because of digestion by proteolytic enzymes and inhibitory effects. Stabilization of factor VIIa against trypsin (a model proteolytic enzyme) and chloromethyl ketone-type inhibitor was accomplished by conjugation of the factor to the gamma-Fe(2)O(3) nanoparticles. This stabilization may extend the blood half-life of factor VIIa. Therefore, IV injection of factor VIIa conjugated gamma-Fe(2)O(3) nanoparticles instead of free factor may avoid the frequent dosing and reduce the cost of hemophilia treatment.

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Influence of Factor VIIa and Phospholipids on Coagulation in “Acquired” Hemophilia

Cited by 58 publications

References 37 publications

Testing of Intravenous Hemostatic Agents in a Novel Swine Model of Bleeding: Preliminary Results With FXa-PCPs

Testing of Intravenous Hemostatic Agents in a Novel Swine Model of Bleeding: Preliminary Results With FXa-PCPs

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

Synthesis and characterization of recombinant factor VIIa‐conjugated magnetic iron oxide nanoparticles for hemophilia treatment

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