Anti-Inhibitor Coagulant Complex, Prothrombin Complex Concentrate, and Recombinant Factor VIIa Reverse Prothrombin Time Prolonged by Edoxaban In Human Plasma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3319-3319 ◽  
Author(s):  
Yoshiyuki Morishima ◽  
Yuko Honda ◽  
Toshiro Shibano
Keyword(s):  
Prothrombin Time ◽  
Human Plasma ◽  
Maximum Concentration ◽  
Prothrombin Complex Concentrate ◽  
Recombinant Factor Viia ◽  
Factor Viia ◽  
Factor Xa ◽  
Anticoagulant Effect ◽  
Hemostatic Agents

Abstract Abstract 3319 Background: Hemorrhage is an unwanted effect of any anticoagulant. In animal studies, edoxaban, a novel direct factor Xa (FXa) inhibitor, does not cause significant bleeding at therapeutic doses; however at higher than 10-times the doses the compound prolongs bleeding time. In clinical studies, edoxaban causes bleeding complications comparable to standard anticoagulants, warfarin and enoxaparin in patients with atrial fibrillation and patients undergoing orthopedic surgery. In case of emergency, antidotes to reverse the anticoagulant effect of edoxaban would be helpful. Objective: To determine the effects of three hemostatic agents: anti-inhibitor coagulant complex, prothrombin complex concentrate, and recombinant factor VIIa (rFVIIa) on prothrombin time (PT) prolonged by edoxaban using pooled human plasma in vitro. Materials & Methods: Anti-inhibitor coagulant complex (Feiba), prothrombin complex concentrate (PPSB-HT), and rFVIIa were purchased from Baxter, Nihon Pharmaceutical, and Novo Nordisk Pharma. Pooled human normal plasma was obtained from George King Bio-Medical. PT was measured with a microcoagulometer (Amelung KC-10A micro) as follows. Five μL of anti-inhibitor coagulant complex, prothrombin complex concentrate, and rFVIIa solutions or vehicle (saline) and 45 μL of plasma spiked with edoxaban or 5% DMSO-saline solution were added to a cuvette and pre-incubated at 37°C for 1 min. Coagulation was started by the addition of 100 μL of HemosIL PT-fibrinogen HS PLUS (Instrumentation Laboratory) to the mixture. The clotting time was measured. Results: Mean PT of the control plasma in three experiments was 17.8 − 18.4 sec. Edoxaban at concentrations of 150 and 300 ng/mL significantly prolonged PT. Addition of anti-inhibitor coagulant complex (0.15, 0.5 and 1.5 U/mL) significantly and concentration-dependently shortened the prolonged PT caused by edoxaban. At the maximum concentration (1.5 U/mL), anti-inhibitor coagulant complex reversed PT to 19.5 and 25.0 sec from 31.5 and 43.7 sec in the presence of 150 and 300 ng/mL edoxaban, respectively. Prothrombin complex concentrate (0.15, 0.5 and 1.5 U/mL) and rFVIIa (100, 300 and 1000 ng/mL) also significantly and concentration-dependently reversed anticoagulant effect of edoxaban. At the maximum concentration of prothrombin complex concentrate (1.5 U/mL), PT was shortened to 23.7 and 31.6 sec from 30.7 and 42.5 sec in the presence of 150 and 300 ng/mL edoxaban. rFVIIa at the maximum concentration (1000 ng/mL) reversed PT to 17.3 and 24.2 sec from 30.7 and 43.1 sec in the presence of 150 and 300 ng/mL edoxaban. Anti-inhibitor coagulant complex, prothrombin complex concentrate and rFVIIa each alone significantly shortened PT in a concentration-dependent manner. In the presence of anti-inhibitor coagulant complex (1.5 U/mL), prothrombin complex concentrate (1.5 U/mL), and rFVIIa (1000 ng/mL), PT was 13.1, 15.1, and 11.6 sec, respectively. Conclusions: The present study demonstrates that anti-inhibitor coagulant complex, prothrombin complex concentrate, and rFVIIa effectively reversed the anticoagulant effect of edoxaban in pooled human plasma in vitro. Therefore, it is suggested that these hemostatic agents have the potential to be antidotes to edoxaban in cases of hemorrhage. Disclosures: Morishima: Daiichi Sankyo Co., Ltd.: Employment. Off Label Use: Drugs: anti-inhibitor coagulant complex, prothrombin complex concentrate, and recombinant factor VIIa Purpose: Reversal of the anticoagulant effect of edoxaban, a factor Xa inhibitor. Honda:Daiichi Sankyo Co., Ltd.: Employment. Shibano:Daiichi Sankyo Co., Ltd.: Employment.

How I treat target-specific oral anticoagulant–associated bleeding

Blood ◽  
2014 ◽  
Vol 123 (8) ◽  
pp. 1152-1158 ◽  
Author(s):  
Deborah M. Siegal ◽  
David A. Garcia ◽  
Mark A. Crowther
Keyword(s):  
Prothrombin Complex Concentrate ◽  
Clinical Evidence ◽  
Recombinant Factor Viia ◽  
Factor Viia ◽  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Supportive Therapy ◽  
Factor Xa ◽  
Low Molecular Weight ◽  
Life Threatening

Abstract Target-specific oral anticoagulants (TSOACs) that directly inhibit thrombin (dabigatran) or factor Xa (rivaroxaban, apixaban) are effective and safe alternatives to vitamin K antagonists (VKAs) and low-molecular-weight heparin (LMWH). Although these agents have practical advantages compared with VKAs and LMWH, there are no antidotes that reverse their anticoagulant effect. Clinical evidence for the efficacy of nonspecific therapies that promote formation of fibrin (prothrombin complex concentrate [PCC], activated PCC [aPCC], and recombinant factor VIIa) in the setting of TSOAC-associated bleeding is lacking, and these prohemostatic products are associated with a risk of thrombosis. In the absence of specific antidotes, addition of PCC or aPCC to maximum supportive therapy may be reasonable for patients with severe or life-threatening TSOAC-associated bleeding. Targeted antidotes for these agents are in development.

Dabigatran and its reversal with recombinant factor VIIa and prothrombin complex concentrate: A Sonoclot in vitro study

2014 ◽  
Vol 74 (7) ◽  
pp. 591-598 ◽  
Author(s):  
Sacha Sølbeck ◽  
Caroline U. Nilsson ◽  
Martin Engström ◽  
Sisse R. Ostrowski ◽  
Pär I. Johansson
Keyword(s):  
Prothrombin Complex Concentrate ◽  
Recombinant Factor Viia ◽  
Factor Viia ◽  
In Vitro Study ◽  
Vitro Study

Possible Synergy between Recombinant Factor VIIa and Prothrombin Complex Concentrate in Hemophilia Therapy

2002 ◽  
Vol 88 (07) ◽  
pp. 60-65 ◽  
Author(s):  
Beverly Christie ◽  
Nicole Henderson ◽  
Nigel Key ◽  
Gary Nelsestuen
Keyword(s):  
Prothrombin Complex Concentrate ◽  
Recombinant Factor Viia ◽  
Factor Viia ◽  
Sequential Therapy ◽  
The United States ◽  
In Vitro Test ◽  
Compassionate Use ◽  
Strong Response ◽  
Vitro Test

SummaryRecombinant factor VIIa (rFVIIa; Novoseven™) is used for treatment of hemophilia patients with inhibitors. There are poorly defined differences in clinical responsiveness between individuals. Prior to licensure in the United States, rFVIIa was available through the compassionate use program, during which two patients described in this study demonstrated an excellent response. More recently, one of these individuals showed a sub-optimal response to rFVIIa. One possible explanation for different treatment outcomes was sequential therapy with prothrombin complex concentrates (PCC) followed by rFVIIa in the compassionate use program. In support of this, an in vitro test showed that this patient had an exceptionally strong response to rFVIIa when it was added to whole blood after the patient received PCC therapy. Results with other patients supported this hypothesis. With further evaluation, a therapeutic approach combining sequential PCC and rFVIIa may prove useful for treatment of bleeding refractory to either agent used alone.

Reversal Of Dabigatran By Recombinant Factor VIIa Is Dependent On The Amount Of Tissue-Factor

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1149-1149 ◽  
Author(s):  
Xena X Li ◽  
Ivan Stevic ◽  
Frank M.H. Lee ◽  
Keith K. Lau ◽  
Anthony K.C. Chan ◽  
...  
Keyword(s):  
Animal Models ◽  
Tissue Factor ◽  
Recombinant Factor Viia ◽  
Conflicts Of Interest ◽  
Factor Viia ◽  
In Vivo Studies ◽  
Bleeding Complications ◽  
Hemostatic Agents

Abstract Background Dabigatran is a new oral anticoagulant that specifically and reversibly inhibits thrombin. Its predictable pharmacokinetics and pharmacodynamics allow for minimal monitoring. However, there is currently no specific antidote to reverse its anticoagulant effects. Instead, activated prothrombin complex concentrate (aPCC) or recombinant Factor VIIa (rFVIIa) has been used to stop bleeding complications in patients on dabigatran. Both were originally used to treat hemophilia patients with inhibitors. Currently, Factor Eight Inhibitor Bypass Activity (FEIBA) is the only clinically approved aPCC, which contains Factors II, IX, X, and VII in both active and non-active forms. In contrast, rFVIIa is a human recombinant protein which can initiate clotting via the tissue factor (TF) pathway. It has been controversial which of these hemostatic agents is more efficient at reversing the effect of dabigatran, as animal models have failed to yield consistent results. We hereby utilized a modified Hemoclot turbdity assay to determine the equivalent concentrations of FEIBA and rFVIIa that can reverse the anticoagulant effect of dabigatran. Methods A mixture was prepared by incubating normal pooled plasma (NPP) with 382 nM dabigatran and varying concentration of hemostatic agents (FEIBA or rFVIIa), in the absence or presence of TF (Thrombosel®). The mixture was diluted 1:8 in TSP buffer, from which a 50 µL-aliquot was then incubated with 100 µL of NPP at 37°C for 5 min. Clotting was initiated with 100 µL of another mixture containing 10 mM Ca2+ and 2.5 nM thrombin in TSP. Turbidity was measured at 350 nm using a SpectraMax Pro spectrophotometer at 37°C for 2 hr. Clotting time (CT) was defined as the time to reach half of the maximum turbidity. Results In this modified Hemoclot turbidity assay, the CT without dabigatran was 101 s and it linearly increased dependent on the dabigatran concentration up to 1500 nM. Dabigatran at 382 nM, the therapeutic plasma concentration, prolonged CT 5-fold to 505 s. Addition of 1 U/mL FEIBA reduced the CT approximately 35% to 328 s. The reversal effect of FEIBA plateaued at 2.5 U/mL to 5 U/mL because there was minimal further reduction in the CT even with 10 U/mL FEIBA. In contrast, rFVIIa at a therapeutic concentration of 50 nM barely reduced the CT by <10% to 469 s. The reversal effects of rFVIIa were drastically enhanced by the addition of extrinsic tissue factor. With TF at 1.5 pM, the rFVIIa reduced the CT to a level similarly achieved by 1 U/mL of FEIBA, but the CT could not be reduced further despite the concentration of rFVIIa increased 10-fold to 400 nM. Finally, although both FEIBA and rFVIIa/TF reached an eventual plateau in the reversal of dabigatran, none of them could lower the CT to the baseline level. Summary/Conclusions Our in vitro study shows that reversal of dabigatran by rFVIIa is dependent on the concentration of TF. Higher levels of TF augment the reversal effects of rFVIIa to the extents similarly achieved with FEIBA. The data may, in part, explain the inconsistency of results obtained from in vivo studies using various animal models to compare rFVIIa and FEIBA for the reversal of dabigatran. The circulating TF levels in vivo are much lower than the amount of TF used in this study, thus its availability in the microenvironment for hemostasis varies depending on the methods used to induce bleeding. The data in this study also explain the variable clinical efficacy of rFVIIa reported in the literature when it is used to reverse the bleeding complications in patients on dabigatran. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Management of the Bleeding Patient Receiving New Oral Anticoagulants: A Role for Prothrombin Complex Concentrates

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Lisa M. Baumann Kreuziger ◽  
Joseph C. Keenan ◽  
Colleen T. Morton ◽  
David J. Dries
Keyword(s):  
Recombinant Factor Viia ◽  
Factor Viia ◽  
Oral Anticoagulants ◽  
New Oral Anticoagulants ◽  
Coagulation Cascade ◽  
Clotting Factors ◽  
Prothrombin Complex Concentrates ◽  
Clotting System ◽  
Clinical Trial Evidence

Ease of dosing and simplicity of monitoring make new oral anticoagulants an attractive therapy in a growing range of clinical conditions. However, newer oral anticoagulants interact with the coagulation cascade in different ways than traditional warfarin therapy. Replacement of clotting factors will not reverse the effects of dabigatran, rivaroxaban, or apixaban. Currently, antidotes for these drugs are not widely available. Fortunately, withholding the anticoagulant and dialysis are freqnently effective treatments, particularly with rivaroxaban and dabigatran. Emergent bleeding, however, requires utilization of Prothrombin Complex Concentrates (PCCs). PCCs, in addition to recombinant factor VIIa, are used to activate the clotting system to reverse the effects of the new oral anticoagulants. In cases of refractory or emergent bleeding, the recommended factor concentrate in our protocols differs between the new oral anticoagulants. In patients taking dabigatran, we administer an activated PCC (aPCC) [FELBA] due to reported benefit in human in vitro studies. Based on human clinical trial evidence, the 4-factor PCC (Kcentra) is suggested for patients with refractory rivaroxaban- or apixaban-associated hemorrhage. If bleeding continues, recombinant factor VIIa may be employed. With all of these new procoagulant agents, the risk of thrombosis associated with administration of factor concentrates must be weighed against the relative risk of hemorrhage.

scholarly journals A Variant of Recombinant Factor VIIa With Enhanced Procoagulant and Antifibrinolytic Activities in an In Vitro Model of Hemophilia

2007 ◽  
Vol 27 (3) ◽  
pp. 683-689 ◽  
Author(s):  
Geoffrey A. Allen ◽  
Egon Persson ◽  
Robert A. Campbell ◽  
Mirella Ezban ◽  
Ulla Hedner ◽  
...  
Keyword(s):  
In Vitro Model ◽  
Recombinant Factor Viia ◽  
Factor Viia ◽  
Vitro Model

Inhibition of fibrinolysis by recombinant factor VIIa in plasma from patients with severe hemophilia A

Blood ◽  
2002 ◽  
Vol 99 (1) ◽  
pp. 175-179 ◽  
Author(s):  
Ton Lisman ◽  
Laurent O. Mosnier ◽  
Thierry Lambert ◽  
Evelien P. Mauser-Bunschoten ◽  
Joost C. M. Meijers ◽  
...  
Keyword(s):  
Hemophilia A ◽  
Recombinant Factor Viia ◽  
Factor Viia ◽  
In Vitro Study ◽  
Clot Lysis ◽  
Severe Hemophilia ◽  
Large Variability ◽  
Lysis Time ◽  
Clot Lysis Time

Recombinant factor VIIa (rFVIIa) is a novel prohemostatic drug for patients with hemophilia who have developed inhibitory antibodies. The postulation has been made that hemophilia is not only a disorder of coagulation, but that hyperfibrinolysis due to a defective activation of thrombin activatable fibrinolysis inhibitor (TAFI) might also play a role. In this in vitro study, the potential of rFVIIa to down-regulate fibrinolysis via activation of TAFI was investigated. rFVIIa was able to prolong clot lysis time in plasmas from 17 patients with severe hemophilia A. The prolongation of clot lysis time by rFVIIa was completely abolished by addition of an inhibitor of activated TAFI. The concentration of rFVIIa required for half maximal prolongation of clot lysis time (Clys½-VIIa) varied widely between patients (median, 73.0 U/mL; range, 10.8-250 U/mL). The concentration of rFVIIa required for half maximal reduction of clotting time (Cclot½-VIIa) was approximately 10-fold lower than the Clys½-VIIa value (median, 8.4 U/mL; range, 1.7-22.5 U/mL). Inhibition of TFPI with a polyclonal antibody significantly decreased Clys½-VIIa values (median, 2.6 U/mL; range, 0-86.9 U/mL), whereas Cclot½-VIIa values did not change (median, 7.2 U/mL; range, 2.2-22.5 U/mL). On addition of 100 ng/mL recombinant full-length TFPI, a nonsignificant increase of Clys½-VIIa values was observed (median, 119.2 U/mL; range, 12.3-375.0 U/mL), whereas Cclot½-VIIa values did not change (median, 8.8 U/mL; range, 2.6-34.6 U/mL). In conclusion, this study shows that rFVIIa both accelerates clot formation and inhibits fibrinolysis by activation of TAFI in factor VIII-deficient plasma. However, a large variability in antifibrinolytic potential of rFVIIa exists between patients.

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