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.

scholarly journals Four-Factor Prothrombin Complex Concentrate (4F-PCC) Effectively Reverses Rivaroxaban Induced Bleeding in a Rabbit Model of Acute Bleeding

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4220-4220
Author(s):  
Eva Herzog ◽  
Jochen Mueller-Cohrs ◽  
Franz Kaspereit ◽  
Wilfried Krege ◽  
Peter Niebl ◽  
...  
Keyword(s):  
Thrombin Generation ◽  
Blood Clotting ◽  
Prothrombin Complex Concentrate ◽  
Rabbit Model ◽  
Off Label Use ◽  
Clotting Time ◽  
Acute Bleeding ◽  
Off Label

Abstract Rivaroxaban is an oral, selective direct factor Xa inhibitor approved for several indications in patients at risk of thrombotic events. One limitation of this agent is the lack of data pertaining to its reversal in situations where urgent response is critical (e.g. acute bleeding events or emergency surgery). This study therefore evaluated the effectiveness of a four-factor prothrombin complex concentrate (4F-PCC; Beriplex® P/N, Kcentra®, CSL Behring), for the reversal of rivaroxaban-associated bleeding in an in vivo rabbit model of acute bleeding. In addition, the study evaluated the correlation between in vitro coagulation parameters and haemostasis in vivo in order to gain more information on the predictivity of in vitro markers for effective bleeding reversal. Administration of single intravenous doses of rivaroxaban (150–450 μg/kg) resulted in increased and prolonged bleeding following standardised kidney injury compared to a vehicle treated control group as determined by measurements of total blood loss and time required to achieve full hemostasis. Subsequent treatment with 4F-PCC (25−100 IU/kg) resulted in a dose-dependent reversal of rivaroxaban-associated bleeding signals. Of the in vitro coagulation markers tested, thrombin generation (TGA) and whole blood clotting time (WBCT) correlated well with in vivo measures of PCC-mediated effects. Thrombin generation was highly reagent-dependent, with the assay initiated using tissue factor reagent being most sensitive to the anticoagulant effects induced by Rivaroxaban, while the phospholipid-only reagent being the most predictive of 4F-PCC mediated effective haemostasis in vivo. In summary, in a rabbit model of acute bleeding, 4F-PCC was able to effectively reduce bleeding to control levels following rivaroxaban 150 μg/kg and 300 μg/kg administrations. The 4F-PCC mediated bleeding reversal correlated best with the in vitro endpoints thrombin generation and whole blood clotting time. Disclosures Herzog: CSL Behring GmbH: Employment. Off Label Use: The use of Beriplex P/N for reversal of Rivaroxaban anticoagulation represents off-label use. Mueller-Cohrs:CSL Behring GmbH: Employment. Kaspereit:CSL Behring GmbH: Employment. Krege:CSL Behring GmbH: Employment. Niebl:CSL Behring GmbH: Employment. Doerr:CSL Behring GmbH: Employment. Schulte:CSL Behring GmbH: Employment. Dickneite:CSL Behring GmbH: Employment.

Anticoagulant Kinetics Following Bolus Injection of Heparin

1979 ◽  
Vol 42 (04) ◽  
pp. 1248-1260 ◽  
Author(s):  
Lyle F Mockros ◽  
Samuel D Hirsch ◽  
Leon Zuckerman ◽  
Joseph A Caprini ◽  
William P Robinson ◽  
...  
Keyword(s):  
Whole Blood ◽  
Blood Clotting ◽  
Anticoagulant Effect ◽  
Post Injection ◽  
Clotting Time ◽  
Sequential Samples ◽  
Dose Dependent ◽  
Blood Clotting Time

SummaryBolus injections of beef-lung heparin at doses of 50, 100 and 200 u/kg body weight were administered to mongrel dogs. Neutralization of the anticoagulant effect was evaluated using sequential samples withdrawn from the animals (in vivo samples) and aliquots from a 100 ml sample withdrawn from the dog at 30 minutes post-injection (in vitro samples). Tests of the activated partial thromboplastin time (APTT) and prothrombin time (PT) did not indicate the degree of anticoagulation. Tests of the whole blood clotting time (WBCT), celite- activated whole blood clotting time (ACT), and celite-activated thromboelastography (ATEG) indicated pronounced hypocoagulability immediately after the injection, followed by a fairly rapid decay in anticoagulability, and a slight Ziype/coagulability at three to four hours post injection. The results from the in vitro ATEG samples were essentially identical to those on the in vivo samples, whereas the in vitro WBCT and ACT generally indicated higher degrees of anticoagulation. Calculated half-lives of the anticoagulant effect are significantly shorter than previously reported, being 18 to 36 minutes, and slightly dose dependent. The decay of the effects, however, does not appear to follow a single exponential curve, dropping very rapidly immediately post-injection and at a somewhat slower rate 60 or more minutes post-injection.

Addition of Prothrombin to Blood from Dogs Receiving Dicumarol

1965 ◽  
Vol 13 (01) ◽  
pp. 187-193 ◽  
Author(s):  
Heinz Schröer ◽  
D. L Heene ◽  
W. H Seegers
Keyword(s):  
Prothrombin Time ◽  
Whole Blood ◽  
Glass Surface ◽  
Blood Clotting ◽  
Factor Ix ◽  
Clotting Time ◽  
Dog Plasma ◽  
Glass Tubes ◽  
Dog Blood ◽  
Blood Clotting Time

SummaryThe prothrombin concentration of dog plasma was lowered by giving large doses of Dicumarol. The dog blood was then mixed with progressive increments of purified bovine prothrombin. When the concentration of prothrombin was equivalent to normal the whole blood clotting time and the prothrombin time were normal. The purified prothrombin supplied all that was essential and did not add detectable amounts of extraneous pro coagulant power. The residual prothrombin in the serum was generally higher when clotting occurred in silicone lined test tubes than in glass. In silicone tubes very little hemophilia B (factor IX, autoprothrombin II) activity developed. This activity was found in the glass tubes in a concentration proportional to the original prothrombin added. The transformation of prothrombin to autoprothrombin II occurred in plasma when there was a glass surface.

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.

Autoprothrombin II of human origin

1961 ◽  
Vol 201 (4) ◽  
pp. 660-662 ◽  
Author(s):  
Orhan N. Ulutin ◽  
J. Frederic Johnson ◽  
Walter H. Seegers
Keyword(s):  
Whole Blood ◽  
Blood Clotting ◽  
Human Origin ◽  
Clotting Time ◽  
Generation Test ◽  
Blood Clotting Time

Autoprothrombin II activity develops when prothrombin preparations of human origin are activated with purified thrombin at pH 8.2. Early during the activation an inhibitor seems to form. Concentrates of the autoprothrombin II can replace serum in the thromboplastin generation test provided platelets are used in the test, but not if a soy bean phosphatide is used. Dogs were given Coumadin in doses that lowered their own autoprothrombin concentration practically to zero. Then while continuing with use of the drug some purified autoprothrombin II was infused intravenously. This was tolerated very well. The autoprothrombin II concentration stayed at normal for 7 hr. In 24 hr none remained. The infusion was also followed by a shortening of the whole blood clotting time.

Heparin Concentrations Correlated To The Activated Whole Blood Clotting Time (Act) During Extracorporeal Circulation

1981 ◽  
Author(s):  
S Stenbjerg ◽  
E Berg ◽  
O K Albrechtsen
Keyword(s):  
Extracorporeal Circulation ◽  
Whole Blood ◽  
Blood Clotting ◽  
Heart Surgery ◽  
Open Heart Surgery ◽  
Open Heart ◽  
Excellent Correlation ◽  
Clotting Time ◽  
Automated Method ◽  
Blood Clotting Time

Heparin levels and ACT were followed during open heart surgery in lo patients. Heparin was assayed by an amidolytic method using substrate S-2222. ACT was determined with an automated method using celite and glass beads as activators of coagulation. Neither the hemodilution nor the depletion of platelets observed during extracorporeal circulation seemed to influence the ACT. An excellent correlation between the ACT and the actual heparin level was found in each patient with coefficients of correlation ranging from 0.73 – 0.97. A slightly better correlation was noticed for values of ACT below 600 seconds. It was concluded that the ACT is a valuable and reliable tool in control of heparinisation during open heart surgery.

Role of Trisodium Citrate in the Unclottability by Thrombin of Fibrinogen Metz

1975 ◽  
Author(s):  
C. Soria ◽  
J. Soria ◽  
M. Samama ◽  
E. Poirot ◽  
G. Kling
Keyword(s):  
Calcium Chloride ◽  
Whole Blood ◽  
Blood Clotting ◽  
Negative Charge ◽  
Trisodium Citrate ◽  
Thrombin Time ◽  
Clotting Time ◽  
Fibrin Formation ◽  
Blood Clotting Time

In a case of homozygous dysfibrinogenemia, the whole blood clotting time was moderately prolonged, while the thrombin clotting time was infinite, whatever dose or nature of thrombin used. Besides, the bleeding syndrome in this case was very weak.We observed also that only after trisodium citrate addition to purified fibrinogen, the abnormal fibrinogen became unclottable by thrombin even after addition of calcium chloride, since without trisodium citrate thrombin time was only prolonged.By immunoelectrophoresis and by isofocusing in the presence or in the absence of trisodium citrate, we therefore undertook to show that trisodium citrate reacts more strongly with the abnormal fibrinogen than with normal one. Thus, trisodium citrate conferring a negative charge to the pathological molecule, the abnormal fibrinogen became resistant to clotting with thrombin. Protamine sulfate, by positiving the charges of fibrinogen, partially corrects the defect in fibrin formation.

Anticlotting activity of phosvitin on chicken blood in vitro

1962 ◽  
Vol 203 (6) ◽  
pp. 1170-1172 ◽  
Author(s):  
Koji Sato ◽  
Kazutaka Homma ◽  
Jiro Gotoh
Keyword(s):  
Whole Blood ◽  
Blood Clotting ◽  
Egg Yolk ◽  
Clotting Time ◽  
Chicken Blood ◽  
Blood Clotting Time

Phosvitin, a phosphoprotein isolated from the vitellin of egg yolk, prolonged the whole blood clotting time in the chicken blood in vitro. The degree of phosvitin's inhibition of coagulation was inversely related to the level of egg-yolk-like material in plasma induced by estrogen.

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