scholarly journals Evaluation of Prothrombin Complex Concentrate and Recombinant Activated Factor VII to Reverse Rivaroxaban in a Rabbit Model

2012 ◽  
Vol 116 (1) ◽  
pp. 94-102 ◽  
Author(s):  
Anne Godier ◽  
Anastasia Miclot ◽  
Bernard Le Bonniec ◽  
Marion Durand ◽  
Anne-Marie Fischer ◽  
...  
Keyword(s):  
Blood Loss ◽  
Thrombin Generation ◽  
Prothrombin Complex Concentrate ◽  
Bleeding Time ◽  
Rabbit Model ◽  
Factor Vii ◽  
Clotting Time ◽  
Recombinant Activated Factor Vii ◽  
Cyclic Flow ◽  
Activated Factor Vii

Background As a potent anticoagulant agent, rivaroxaban exposes a risk of bleeding. An effective way to reverse its effects is needed. Objectives were to study efficacy and safety of recombinant activated factor VII (rFVIIa) and prothrombin complex concentrate (PCC) to reverse the anticoagulant effect of an overdose of rivaroxaban in a rabbit model of bleeding and thrombosis. Methods First, a dose-ranging study assessed the minimal rivaroxaban dose that increased bleeding. Then, 48 anesthetized and ventilated rabbits were randomized into four groups: control (saline), rivaroxaban (rivaroxaban and saline), rFVIIa (rivaroxaban and rFVIIa), and PCC (rivaroxaban and PCC). The Folts model was applied: a stenosis and an injury were carried out on the carotid artery, inducing thrombosis, detected as cyclic flow reductions, which were recorded over 20 min. Then the following were measured: ear immersion bleeding time, clotting times, anti-Xa activity, thrombelastometric parameters, and thrombin generation test. Ultimately, a hepatosplenic section was performed and the total amount of blood loss after 15 min was evaluated as primary endpoint. Results Rivaroxaban increased blood loss (17 g [8-32] vs. 7 g [5-18] for control (median [range]), P = 0.0004), ear bleeding time, clotting times, thrombelastographic clotting time, and decreased thrombin generation. In contrast, rFVIIa decreased ear bleeding time (92 s [65-115] vs. 140 s [75-190], P < 0.02), but without efficacy on blood loss. PCC and rFVIIa decreased activated partial thromboplastin time as well as thrombelastographic clotting time. Regarding safety, neither rFVIIa nor PCC increased cyclic flow reductions. Conclusion rFVIIa and PCC partially improved laboratory parameters, but did not reverse rivaroxaban induced-bleeding.

Efficacy of prothrombin complex concentrate to reverse the anticoagulant effect of the pentasaccharide fondaparinux in a rabbit model

2011 ◽  
Vol 105 (01) ◽  
pp. 161-168 ◽  
Author(s):  
Marion Durand ◽  
Joseph Emmerich ◽  
Blandine Dizier ◽  
Thomas Lecompte ◽  
Charles-Marc Samama ◽  
...  
Keyword(s):  
Blood Flow ◽  
Blood Loss ◽  
Prothrombin Complex Concentrate ◽  
Bleeding Time ◽  
Rabbit Model ◽  
Anticoagulant Effect ◽  
Efficacy And Safety ◽  
Clotting Time ◽  
Local Blood Flow ◽  
Cyclic Flow

SummaryAs a potent anticoagulant agent, fondaparinux exposes a risk of bleeding. An effective way to reverse its effects is needed. It was the objective to study efficacy and safety of prothrombin complex concentrate (PCC) to reverse the anticoagulant effect of fondaparinux in a rabbit model of bleeding and thrombosis. In anaesthetised and ventilated rabbits, the Folts model was applied: a stenosis (75%) and an injury were carried out on the carotid artery, inducing thrombosis. Blood flow decreased as thrombus size increased until the pressure gradient was such that the thrombus was released and local blood flow was suddenly restored. This is known as a cyclic flow reduction (CFR). After the first CFR, rabbits were randomised into three groups: control (saline and saline after 1 minute), fondaparinux (fondaparinux [3 mg.kg−1] and saline), PCC (fondaparinux and PCC [40 UI.kg−1]). Then CFRs were recorded over 20 minutes. The following were measured: ear immersion bleeding time (BT), haemoglobin blood level (Hb1) and thrombelasto-metric parameters (ROTEM®). Finally, a hepatosplenic section was performed; 15 minutes later, the amount of blood loss was recorded as primary endpoint and Hb2 was measured. Blood loss was increased with fondaparinux and normalised with PCC. Regarding ROTEM® INTEM, fondaparinux increased clotting time and clotting formation time. PCC normalised these parameters. EXTEM and FIBTEM tests were not modified. Regarding safety, PCC did not increase CFRs. PCC reduced bleeding without increasing thrombosis and was effective to reverse the haemorrhagic effect of fondaparinux in this rabbit model.

Effective Reversal of Edoxaban-associated Bleeding with Four-factor Prothrombin Complex Concentrate in a Rabbit Model of Acute Hemorrhage

2015 ◽  
Vol 122 (2) ◽  
pp. 387-398 ◽  
Author(s):  
Eva Herzog ◽  
Franz Kaspereit ◽  
Wilfried Krege ◽  
Baerbel Doerr ◽  
Jochen Mueller-Cohrs ◽  
...  
Keyword(s):  
Blood Loss ◽  
Prothrombin Time ◽  
Whole Blood ◽  
Thrombin Generation ◽  
Blood Clotting ◽  
Prothrombin Complex Concentrate ◽  
Rabbit Model ◽  
Clotting Time ◽  
Blood Clotting Time

Abstract Background: Edoxaban is an oral, selective direct factor Xa inhibitor approved in Japan for venous thromboembolism prevention after orthopedic surgery. Data are lacking regarding reversal strategies for edoxaban; this study assessed whether four-factor prothrombin complex concentrate (Beriplex®/Kcentra®; CSL Behring GmbH, Marburg, Germany) can effectively reverse its effects on hemostasis using a previously described rabbit model. Methods: The study comprised assessments of thrombin generation in vitro, pharmacokinetic parameters, and edoxaban reversal in vivo. In a blinded in vivo stage, a standardized kidney incision was performed in animals (n = 11 per group) randomized to receive vehicle + saline, edoxaban (1,200 μg/kg) + saline, or edoxaban (1,200 μg/kg) + four-factor prothrombin complex concentrate (50 IU/kg). Animals were monitored for treatment impact on hemostasis and coagulation parameters. Data are median (range). Statistical tests were adjusted for multiple testing. Results: Edoxaban administration increased blood loss (30 [2 to 44] ml) and time to hemostasis (23 [8.5 to 30.0] min) compared with the control group (3 [1 to 8] ml and 3 [2.0 to 5.0] min, respectively). Biomarkers of coagulation (prothrombin time, activated partial thromboplastin time, whole blood clotting time) and thrombin generation parameters (e.g., peak thrombin, endogenous thrombin potential, lag time) were also affected by edoxaban. Administration of four-factor prothrombin complex concentrate significantly reduced time to hemostasis (to 8 [6.5 to 14.0] min, observed P < 0.0001) and total blood loss (to 9 [4 to 22] ml, observed P = 0.0050) compared with the edoxaban + saline group. Of the biomarkers tested, prothrombin time, whole blood clotting time, and endogenous thrombin potential correlated best with clinical parameters. Conclusion: In a rabbit model of hemostasis, four-factor prothrombin complex concentrate administration significantly decreased edoxaban-associated hemorrhage.

Potential of Activated Prothrombin Complex Concentrate and Activated Factor VII to Reverse the Anticoagulant Effects of Rivaroxaban in Primates

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3825-3825 ◽  
Author(s):  
András Gruber ◽  
Ulla M Marzec ◽  
Ulf Buetehorn ◽  
Stephen Hanson ◽  
Elisabeth Perzborn
Keyword(s):  
Prothrombin Time ◽  
Prothrombin Complex Concentrate ◽  
Bleeding Time ◽  
Fold Increase ◽  
Fold Change ◽  
Factor Vii ◽  
High Dose ◽  
Recombinant Activated Factor Vii ◽  
Activated Factor Vii ◽  
Activated Prothrombin Complex Concentrate

Abstract Rivaroxaban is an oral, direct Factor Xa (FXa) inhibitor that has been recommended for approval by the Committee for Medicinal Products for Human Use for the prevention of venous thromboembolism after elective hip and knee replacement, and is in advanced clinical development for the prevention and treatment of thromboembolic disorders. Because bleeding is a potential side-effect of accidental rivaroxaban overdose, we evaluated whether activated prothrombin complex concentrate (APCC, FEIBA®) and recombinant activated Factor VII (rFVIIa, NovoSeven®) administration could mitigate the antihemostatic effects of high-dose rivaroxaban in juvenile male baboons. Pharmacologic impairment of hemostasis (3- to 4-fold increase in prothrombin time [PT] from baseline and ≥2-fold increase in template bleeding time [BT]) was achieved by an intravenous (i.v.) bolus of rivaroxaban (0.6 mg/kg) followed by continuous infusion (0.6 mg/kg/h) for 60 minutes. At steady-state anticoagulation (30 minutes from bolus), one group of anticoagulated baboons (n=7) received APCC (50 U/kg, over 25 minutes). A second group (n=7) received an i.v. bolus dose of rFVIIa (210 μg/kg) 30 minutes after the start of anticoagulation. Reversal of the antihemostatic effects of supratherapeutic doses of rivaroxaban by APCC and rFVIIa was assessed by measurement of BT and clotting times. In the APCC group, high-dose rivaroxaban prolonged BT to 202% (95% CI±21%; p<0.001) of baseline and PT by 3-fold (Table). On completion of APCC infusion, BT returned to baseline and PT was reduced. In the rFVIIa group, rivaroxaban prolonged BT to 254% (95% CI±30%; p<0.05). Infusion of rFVIIa reduced BT by 34%, and PT was also shortened. Circulating thrombin–antithrombin complex (TAT) levels decreased during rivaroxaban infusion, and this decrease did not change significantly after rFVIIa bolus administration. However, APCC increased baseline plasma TAT levels, suggesting a systemic hypercoagulation. We conclude that administration of APCC or rVIIa can rapidly attenuate hemostasis impairment after rivaroxaban overdose in baboons, thus providing potential antidotes during bleeding emergencies. Table. The effect of activated prothrombin complex concentrate (APCC) and recombinant activated Factor VII (rFVIIa) on bleeding time (BT), prothrombin time (PT), and thrombin–antithrombin complex concentration (TAT) in baboons anticoagulated with high-dose rivaroxaban (n=7 each). Values are given as mean ± standard deviation Time BT (x-fold change from baseline) PT (x-fold change from baseline) TAT (μg/L) APCC Baseline 1.00 1.00 3.51±0.08 30 minutes after rivaroxaban 2.02±0.56 3.04±0.43 3.01±1.37 At end of APCC infusion 1.02±0.33 2.20±0.29 10.35±1.41 20 minutes after end of APCC infusion 1.65±0.94 2.28±0.29 n.d. rFVIIa Baseline 1.00 1.00 7.35±4.17 30 minutes after rivaroxaban 2.54±0.79 3.17±0.42 2.95±0.79 5 minutes after rFVIIa 1.68±0.80 2.38±0.41 2.58±0.52 30 minutes after rFVIIa 1.96±1.26 2.48±0.49 4.00±1.12

scholarly journals Nebulised recombinant activated factor VII (rFVIIa) does not attenuate the haemorrhagic effects of blast lung injury

2018 ◽  
Vol 165 (1) ◽  
pp. 51-56
Author(s):  
Jason E Smith ◽  
S Watts ◽  
A M Spear ◽  
C Wilson ◽  
E Kirkman
Keyword(s):  
Lung Injury ◽  
Electron Paramagnetic Resonance Spectroscopy ◽  
Rabbit Model ◽  
Factor Vii ◽  
Alveolar Haemorrhage ◽  
Systemic Absorption ◽  
Resonance Spectroscopy ◽  
Recombinant Activated Factor Vii ◽  
Activated Factor Vii ◽  
Blast Lung Injury

IntroductionPrimary blast lung injury causes intrapulmonary haemorrhage. A number of case reports have suggested the efficacy of recombinant activated factor VII (rFVIIa) in the treatment of diffuse alveolar haemorrhage from a range of medical causes, but its efficacy in blast lung is unknown. The aim of this study was to investigate whether nebulised rFVIIa attenuates the haemorrhagic effects of blast lung injury in an animal model.MethodsTerminally anaesthetised rabbits subjected to blast lung injury were randomised to receive either rFVIIa or placebo via a nebuliser. The primary outcome was the level of blood iron–transferrin complex, a marker of the extent of blast lung injury, analysed using low temperature electron paramagnetic resonance spectroscopy.ResultsBlast exposure led to a significant fall in iron-bound transferrin in both groups of animals (p<0.001), which remained depressed during the study. There were no significant differences in iron–transferrin between the rFVIIa and placebo treatment groups over the duration of the study (p=0.081), and there was no trend towards elevated iron–transferrin in the rFVIIa-treated group once drug treatment had started. There was suggestive evidence of systemic absorption of rFVIIa given via the inhaled route.ConclusionA single dose of nebulised rFVIIa did not attenuate pulmonary haemorrhage in a rabbit model of blast lung injury. As there was some evidence of systemic absorption, the inhaled route does not avoid the concern about potential thromboembolic complications from administration of rFVIIa.

Injection of recombinant activated factor VII can induce transient increase in circulating procoagulant microparticles

2004 ◽  
Vol 91 (05) ◽  
pp. 873-878 ◽  
Author(s):  
Bénédicte Hugel ◽  
Benoit Guillet ◽  
Catherine Trichet ◽  
Anne Rafowicz ◽  
Thierry Lambert ◽  
...  
Keyword(s):  
Short Duration ◽  
Platelet Activation ◽  
Thrombin Generation ◽  
Transient Increase ◽  
Factor Vii ◽  
Recombinant Activated Factor Vii ◽  
Activated Factor Vii ◽  
Therapeutic Doses

SummaryRecombinant activated factor VII (rFVIIa) is an effective haemostatic treatment in haemophiliacs with inhibitors. In vitro, FVIIa concentrations corresponding to those obtained with therapeutic doses of rFVIIa have been shown to induce normal thrombin generation and platelet activation in the absence of factors VIII or IX. To further study the in vivo haemostatic changes induced by rFVIIa, circulating procoagulant microparticles (MP) were measured in patients treated with discontinuous injections of Novoseven®. In 6 out of 15 patients, a transient peak of procoagulant MP was observed after injection, occurring 15 min to 2 h after infusion. It was composed primarily of platelet-derived MP and was of very short duration. This peak was not observed in haemophiliacs without inhibitor, who were treated with conventional replacement therapies. Our results provide further in vivo evidence that rFVIIa specifically activates platelets, either directly or as a consequence of a burst of thrombin generation that could account for its haemostatic efficacy.

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