Anne-Céline Martin

Evaluation of recombinant activated factor VII, prothrombin complex concentrate, and fibrinogen concentrate to reverse apixaban in a rabbit model of bleeding and thrombosis

BACKGROUNDnAs all anticoagulants, apixaban exposes to a bleeding risk, thus an effective way to reverse its effects is needed. Objectives were to study efficacy and safety of recombinant activated factor VII (rFVIIa), prothrombin complex concentrate (PCC), and fibrinogen concentrate (Fib) to reverse apixaban in a rabbit model of bleeding and thrombosis.nnnMETHODSnAfter a dose-ranging study to assess the minimal amount of apixaban increasing bleeding, 63 anaesthetized rabbits were randomized into 5 groups: control (saline), apixaban (apixaban and saline), rFVIIa (apixaban and rFVIIa), PCC (apixaban and PCC) and fibrinogen (apixaban and Fib). The Folts model was applied: a stenosis and an injury were carried out on the carotid artery, inducing thrombosis detected as cyclic flow reductions (CFRs) within 20 min. A number of parameters were recorded through ear immersion bleeding time (BT), clotting times (CT), thrombelastography, and thrombin generation time (TGT). Ultimately, a hepatosplenic section was performed to evaluate as primary endpoint the blood loss in 15 min.nnnRESULTSnApixaban increased blood loss (11.6 ± 3 g vs. 8.3 ± 3 g for control, p < 0.0003), lengthened BT, the prothrombin time (PT), thrombelastographic CT and decreased thrombin generation. Only rFVIIa reduced BT yet failed to improve blood loss. PCC and rFVIIa both shortened the PT, CT in thrombelastographic, and lag time in TGT. Fib improved clot firmness, enhanced thrombin generation but increased bleeding. Regarding safety, neither rFVIIa, PCC, nor Fib increased CFRs.nnnCONCLUSIONnrFVIIa, PCC, and Fib failed to reverse apixaban-induced bleeding. They only improved several laboratory parameters.

Multimodal assessment of non-specific hemostatic agents for apixaban reversal.

Non‐specific hemostatic agents, namely activated prothrombin complex concentrate (aPCC), PCC and recombinant activated factor (F) VII (rFVIIa), can be used, off‐label, to reverse the effects of FXa inhibitors in the rare cases of severe hemorrhages, as no approved specific antidote is available. We have evaluated the ability of aPCC, PCC and rFVIIa to reverse apixaban.

Peri-procedural management of dabigatran and rivaroxaban: Duration of anticoagulant discontinuation and drug concentrations

BACKGROUNDnPeri-procedural management of direct oral anticoagulants (DOAC) is challenging. The optimal duration of pre-procedural discontinuation that guarantees a minimal DOAC concentration ([DOAC]) at surgery is unknown. The usual 48-hour discontinuation might not be sufficient for all patients.nnnOBJECTIVESnTo test the hypothesis that a 48-hour DOAC discontinuation is not sufficient to ensure a minimal per-procedural [DOAC], defined as [DOAC]<30ng/mL. To investigate the factors associated with per-procedural [DOAC]. To evaluate the ability of normal PT and aPTT to predict [DOAC]<30ng/mL.nnnMETHODSnPatients treated with dabigatran or rivaroxaban, and requiring any invasive procedure were included in this multicentre, prospective, observational study. [DOAC], PT and aPTT were measured during invasive procedure.nnnRESULTSnSixty-five patients were enrolled. Duration of DOAC discontinuation ranged from 1-168h. Per-procedural [DOAC] ranged from <30 to 466ng/mL. [DOAC]<30ng/mL occurred more frequently after 48-hour discontinuation than after a shorter delay. [DOAC] remained ≥30ng/mL in 36% and 14% of measurements performed 24-48h and 48h-120h after discontinuation, respectively. According to ROC curve, a cut-off value of 120hours for DOAC discontinuation had a better specificity than a cut-off value of 48hours to predict [DOAC]<30ng/mL. Normal PT and aPTT ratios had good specificity and positive predictive value, but limited sensitivity (74%) and negative predictive value (73%) to predict [DOAC]<30ng/mL.nnnCONCLUSIONSnA 48-hour discontinuation does not guarantee a [DOAC]<30ng/mL in all patients. Normal PT and aPTT are flawed to predict this threshold and could not replace specific assays. Further studies are needed to define the relationship between per-procedural [DOAC] and clinical outcomes.

Association rate constants rationalise the pharmacodynamics of apixaban and rivaroxaban

Rivaroxaban and apixaban are selective direct inhibitors of free and prothrombinase-bound factor Xa (FXa). Surprisingly prothrombin time (PT) is little sensitive to clinically relevant changes in drug concentration, especially with apixaban. To investigate this pharmacodynamic discrepancy we have compared the kinetics of FXa inhibition in strictly identical conditions (pH 7.48, 37u2009°C, 0.15 M). KI values of 0.74 ± 0.03 and 0.47 ± 0.02 nM and kon values of 7.3 ± 1.6 10(6) and 2.9 ± 0.6 10(7) M(-1) s(-1) were obtained for apixaban and rivaroxaban, respectively. To investigate if these constants rationalise the inhibitor pharmacodynamics, we used numerical integration to evaluate impact of FXa inhibition on thrombin generation assay (TGA) and PT. Simulation predicted that in TGA triggered with 20 pM tissue factor, 100 ng/ml apixaban or rivaroxaban increased 1.8- or 3.0-fold the lag time and 1.4- or 2.0-fold the time to peak, whilst decreasing 1.2- or 3.1-fold the maximum thrombin and 1.7- or 3.5-fold the endogenous thrombin potential. These numbers were consistent with those obtained through the corresponding TGA triggered in plasma spiked with apixaban or rivaroxaban. Simulated PT ratios were also consistent with the corresponding plasma PT: markedly less sensitive to apixaban than to rivaroxaban. Analogous differences in TGA and PT were obtained irrespective of the drug amount added. We concluded that kon values for FXa of apixaban and rivaroxaban rationalise the unexpected lower sensitivity of PT and TGA to the former.

Ticagrelor reversal: in vitro assessment of four haemostatic agents

Aim Management of ticagrelor-induced bleeding is challenging as platelet transfusion is ineffective. An effective strategy is needed. This study aimed to investigate in vitro the efficacy of four haemostatic drugs (HDs), namely recombinant activated factor VII (rFVIIa), fibrinogen concentrate (Fib), tranexamic acid (TXA) and factor XIII concentrate (FXIII) to improve the haemostatic capacity in the presence of ticagrelor. Methods Blood was spiked with ticagrelor then supplemented by either HD or control. Several assays were performed: ADP-induced platelet aggregation measured by impedance aggregometry, light transmission and two global assays, thrombolastography with the platelet mapping device (TEG-PM) and a platelet-dependent thrombin generation assay (TGA). Results Ticagrelor inhibited ADP-induced platelet aggregation and decreased the clot strength maximum amplitude (MA) in TEG-PMADP. None of the HDs corrected these parameters. However, rFVIIa shortened the coagulation time R using TEG-PMthrombin and the time to peak prolonged by ticagrelor in TGA. Fib increased MAthrombin and FXIII decreased LY30. TXA had no effects. Conclusions Whereas none of the HDs corrected ticagrelor-induced platelet inhibition, rFVIIa shortened coagulation times, Fib increased clot firmness and FXIII decreased fibrinolysis. Consequently, they may bypass ticagrelor effects by acting on fibrin formation or fibrinolysis. Further studies are needed to confirm these data in vivo.

Successful Use of Recombinant Activated Factor VII to Reverse Ticagrelor-Induced Bleeding Risk: A Case Report

Management of ticagrelor-associated bleeding is challenging, especially in neurosurgery. Platelet transfusion is inefficient and no antidote is currently available. We report here the first case of recombinant activated factor VII (rFVIIa) use to bypass ticagrelor-induced platelet inhibition. A woman treated with ticagrelor and requiring emergent neurosurgery for an intracranial hematoma received preoperative high-dose platelet transfusion and 60 μg/kg rFVIIa. Laboratory monitoring demonstrated that platelet transfusion failed to reverse ticagrelor-induced platelet inhibition while rFVIIa improved hemostasis by shortening the thromboelastometric clotting time. Neurosurgery occurred without any bleeding event but the patient presented with a postoperative pulmonary embolism. In conclusion, rFVIIa may decrease ticagrelor-induced bleeding risk but careful assessment of the benefit-risk balance is warranted before using rFVIIa to reverse ticagrelor effects.