In vitro reversal of direct factor Xa inhibitors: Direct comparison of andexanet alfa and prothrombin complex concentrates Cofact and Beriplex/Kcentra

Figures

• 

  FIGURE 1. Representative thrombin generation curves obtained in the absence or presence of 200 ng/ml of DOAC with or without reversal agent, being either 0.25 mg/ml andexanet alfa or 1.25 IU/ml 4F‐PCC. Derived parameters lag time, peak thrombin, and ETP are indicated in the upper left figure for the tracing with plasma without DOAC or reversal agent (control: no factor Xa inhibitor and no reversal agent added). For the derived velocity index, this is indicated in the upper middle panel. 4F‐PCC, four‐factor prothrombin complex concentrate; DOAC, direct oral anticoagulant; ETP, endogenous thrombin potential

• 

  FIGURE 2. Thrombin generation parameters obtained at 0–800 ng/ml apixaban or rivaroxaban and in the absence or presence of 1.25 IU/ml of 4F‐PCC (Cofact or Beriplex) or 0.25 mg/ml of andexanet alfa. Data are presented as percentage of control (no DOAC and no reversal agent) and represent the means ± SD of three separate DOAC titration experiments for each of the reversal agents. Horizontal green line: 100% control. Orange bar: 10th–90th percentile of rivaroxaban or apixaban levels in patients presenting with major bleeding. 6 4F‐PCC, four‐factor prothrombin complex concentrate; DOAC, direct oral anticoagulant; ETP, endogenous thrombin potential; SD, standard deviation

• 

  FIGURE 3. Representative fibrin generation‐clot lysis curves obtained in the absence or presence of 200 ng/ml DOAC with or without reversal agent, being either 0.25 mg/ml andexanet alfa or 1.25 IU/ml 4F‐PCC. Derived parameters CT, LT, and CLT are indicated in the upper left figure for the tracing with plain plasma (control: no factor Xa inhibitor and no reversal agent added). 4F‐PCC, four‐factor prothrombin complex concentrate; CLT, clot lysis time CT, clotting time; DOAC, direct oral anticoagulant; LT, lysis time

• 

  FIGURE 4. Clotting time and clot lysis time data obtained at 0–800 ng/ml apixaban or rivaroxaban and in the absence or presence of 1.25 IU/ml of 4F‐PCC (Cofact or Beriplex/Kcentra) or 0.25 mg/ml of andexanet alfa. Data are presented as percentage of control (no DOAC and no reversal agent) and represent the means ± SD of three separate DOAC titration experiments for each of the reversal agents. Horizontal green line: 100% control. Orange bar: 10th‐90th percentile of rivaroxaban or apixaban levels in patients presenting with a major bleeding. 6 4F‐PCC, four‐factor prothrombin complex concentrate; CLT, clot lysis time CT, clotting time; DOAC, direct oral anticoagulant; SD, standard deviation

• 

  FIGURE 5. Thrombin generation parameters, CT and CLT at 200 ng/ml of apixaban or rivaroxaban and increasing andexanet alfa dose (0–0.5 mg/ml). Data are presented as percentage of control (no DOAC and no reversal agent) and represent the means ± SD of three separately performed experiments. Horizontal green line: 100% control. Vertical red lines: andexanet alfa doses corresponding to approximately 400‐mg and approximately 800‐mg bolus. CLT, clot lysis time CT, clotting time; DOAC, direct oral anticoagulant; ETP, endogenous thrombin potential; SD, standard deviation

• 

  FIGURE 6. Peak thrombin, ETP, and CLT data obtained at 0–800 ng/ml of apixaban or rivaroxaban and increasing dose of 4F‐PCC (Cofact or Beriplex/Kcentra). Data are presented as percentage of control (no DOAC and no reversal agent) and represent the means ± SD of three separately performed experiments. Horizontal green line: 100% control. Vertical blue line: advised 4F‐PCC dose of 1.25 IU/ml (50 U/kg bw). 4F‐PCC, four‐factor prothrombin complex concentrate; bw, bodyweight; CLT, clot lysis time CT, clotting time; DOAC, direct oral anticoagulant; ETP, endogenous thrombin potential; SD, standard deviation