Andexanet versus prothrombin complex concentrates: Differences in reversal of factor Xa inhibitors in in vitro thrombin generation

Figures

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  Figure 1. Contribution of individual coagulation factors (FVII, FIX, FX, FII) in 4F‐PCCs to TF–TG in normal plasma with or without rivaroxaban. A, Thrombin generation profiles in normal plasma supplemented with different coagulation factors compared to 4F‐PCCs in the absence of a FXa inhibitor. Purified plasma coagulation factor was added to PPP (0‐1.0 IU/mL); 1.0 IU/mL is equivalent to the normal plasma level of each factor in healthy subjects (the addition of 1.0 IU/mL of an individual factor therefore doubles the plasma concentration of that factor). Addition of FVII or FX had minimal effect whereas FIX (1.0 IU/mL) increased Peak by approximately 60% as would be expected since FIXa can activate additional FX to FXa and accelerate thrombin generation. Addition of FII (1.0 IU/mL) alone increased the ETP similar to that seen with the addition of 4F‐PCC (1.0 IU/mL). Shown are representative thrombin generation profiles with each coagulation factor or 4F‐PCC. B, Contribution of individual coagulation factors (FVII, FIX, FX, FII) to TF–TG in plasma with rivaroxaban. Representative thrombin generation profiles in the presence of rivaroxaban (250 ng/mL) and different levels of coagulation…

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  Figure 2. Effect of 4F‐PCC on TF–TG in the presence of rivaroxaban or apixaban. A, TF‐TG profiles in PCC‐spiked plasma with a FXa inhibitor at ~ Cmax. Representative thrombin generation profiles are shown in the presence of rivaroxaban (250 ng/mL) or apixaban (125 ng/mL) with 4F‐PCC (0‐1.0 IU/mL). B, Effect of 4F‐PCC on FXa inhibitor–induced anticoagulation as assessed by ETP and Peak. Data are shown as mean ± SD (N = 2). The dashed lines represent normal ETP and Peak in PPP. 4F‐PCC, four‐factor prothrombin complex concentrate; Apix, apixaban; Cmax, maximum plasma concentration; ETP, endogenous thrombin potential; FXa, factor Xa; Peak, peak thrombin; PPP, platelet‐poor plasma; Riva, rivaroxaban; SD, standard deviation; TF‐TG, tissue factor–initiated thrombin generation

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  Figure 3. Effect of andexanet on TF‐TG (ETP) in the presence of rivaroxaban or apixaban compared with 4F‐PCCs. A, Rivaroxaban; and B, apixaban. Data are shown as mean ± SD (N = 2). In each panel, the horizontal dashed line represents the ETP level in normal plasma. The vertical dashed line indicates the 75‐ng/mL inhibitor level. The shaded area represents the range of inhibitor levels (75‐1000 ng/mL) found in the ANNEXA‐4 efficacy population (≥75 ng/mL). The inset table shows the plasma level of 4F‐PCC or andexanet at their approved low and high doses, respectively. 4F‐PCC, four‐factor prothrombin complex concentrate; ETP, endogenous thrombin potential; FXa, factor Xa; SD, standard deviation; TF‐TG, tissue factor–initiated thrombingeneration. aAt the approved andexanet low and high doses, the andexanet Cmax is ~2.0 μM at low dose (400‐mg bolus plus 4 mg/min 2‐hour infusion) and ~4.0 μM at high dose (800‐mg bolus plus 8 mg/min × 2‐hour infusion). The 2 and 4 μM levels are maintained by the infusion.

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  Figure 4. Effect of andexanet on TF‐TG (Peak) in the presence of rivaroxaban or apixaban compared with 4F‐PCCs. A, Rivaroxaban; and B, apixaban. Data are shown as mean ± SD (N = 2). In each panel, the horizontal dashed line represents the Peak level in normal plasma. The vertical dashed line indicates the 75‐ng/mL inhibitor level. The shaded area represents the range of inhibitors (75‐1000 ng/mL) found in the ANNEXA‐4 efficacy population (≥75 ng/mL). The inset table shows the plasma level of 4F‐PCC or andexanet at their approved low and high doses, respectively. 4F‐PCC, four‐factor prothrombin complex concentrate; FXa, factor Xa; Peak, peak thrombin; SD, standard deviation; TF‐TG, tissue factor–initiated thrombin generation. aAt the approved andexanet low and high doses, the andexanet Cmax is ~2.0 μM at low dose (400‐mg bolus plus 4 mg/min 2‐hour infusion) and ~4.0 μM at high dose (800‐mg bolus plus 8 mg/min × 2‐hour infusion). The 2 and 4 μM levels are maintained by the infusion.

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  Figure 5. Calculated versus observed effect of 4F‐PCCs on TF–TG (Peak) as a function of FXa inhibitor concentrations. A, Rivaroxaban; and B, apixaban. Data were normalized to normal PPP (100%, horizontal dashed line). For clarity, the results are presented in two separate panels for each inhibitor with or without 4F‐PCCs. The solid line represents the calculated values from Table 2 after taking into account the prothrombin component effect (1.33×). The open circle represents the observed effect of 4F‐PCCs (0, 1.0 IU/mL) on Peak (data from Figure 4). Note that at the same level of inhibitor concentrations, apixaban appears to have less inhibitory effect on thrombin generation compared with rivaroxaban (Figures 2, 3, 4), which could be explained by the different rate of inhibition (kon) in addition to the affinity (Ki) between the two inhibitors. The kon value for apixaban is several‐fold slower than rivaroxaban. 55 The calculations shown in Table 2 and Figure 5 were solely based on Ki and may represent an over‐estimation of the apixaban inhibitory effect compared to rivaroxaban. 4F‐PCC, four‐factor prothrombin complex concentrate; FXa, factor Xa; Peak, peak thrombin; PPP, platelet‐poor…