Combined Antithrombin and Heparin Supplementation to Blood for Restoring Heparin Responsiveness After Andexanet Alfa Exposure: An In Vitro Model

Figures

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  FIGURE 1. ACT measurement (seconds [s]). Andexanet significantly reversed ACT prolongation in on‐CPB blood († p < 0.001). Low‐dose AT supplemented with extra heparin was ineffective in restoring heparin responsiveness. The moderate and high‐dose AT along with extra heparin restored the mean ACT to near or above 400 s (dotted line) (*p < 0.001vs. ANX). ACT, activated clotting time; ANX, andexanet alfa; AT, antithrombin (low, 0.8; moderate, 2.0; and high, 3.1 µM; final concentration in whole blood); CPB, cardiopulmonary bypass; Hep, heparin.

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  FIGURE 2. Graphical representation of INTEM CT (seconds [s]). Data are shown as mean (SD). ANX, andexanet alfa; AT, antithrombin (0.8, 2.0, or 3.1 µM, final concentration in whole blood); CPB, cardiopulmonary bypass; CT, clotting time; Hep, heparin; MCF, maximum clot firmness. †Flatline INTEM shown as CT truncated at 800 s. *p < 0.001versus ANX.

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  FIGURE 3. Representative thrombin generation patterns in on‐CPB plasma. Dashed line shows a TG response neutralized with heparinase. The andexanet‐induced procoagulant effect in on‐CPB plasma was partially reversed by heparin supplementation alone. AT, in combination with extra heparin, mitigated andexanet‐induced heparin resistance in a dose‐dependent manner. With moderate and high levels of AT, marked prolongation of lag time and decreased peak and velocity were observed (*p < 0.001vs. ANX in Table 2). AT, antithrombin (low, 1.1; moderate, 2.8; and high, 4.4 µM; final concentration in plasma); ANX, andexanet alfa; CPB, cardiopulmonary bypass; Hep, heparin; TG, thrombin generation.