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Ibrutinib and acalabrutinib: effects on platelet functions
major reason for discontinuing ibrutinib during the first year of treatment, with this translating into shorter progres- sion-free and overall survivals.29 Management of bleeding is therefore of paramount importance, especially in the 10- 12% of cases who develop atrial fibrillation and require anticoagulation (which increases the risk of grade 3-4 bleed- ing). The second-generation irreversible Btk inhibitor, acal- abrutinib, with less off-target kinase inhibition, is expected
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to improve the safety profile, including bleeding, of Btk inhibition.9,19,24 In this study we characterized the effects of acalabrutinib on platelet functions in vitro and ex vivo and compared these effects with those of ibrutinib.
We performed a series of assays on two populations of healthy donors characterized by high or low sensitivity to ibrutinib, based on the degree of inhibition of collagen- induced platelet aggregation in PRP achieved by the drug.
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Figure 4. Effect of acalabrutinib on platelet thrombus formation ex vivo on collagen under arterial flow. (A, B) DIOC6-labeled platelets from healthy donors with (A) low sensitivity (LS) or (B) high sensitivity (HS) to ibrutinib (determined on the basis of their aggregation response as in Figure 1) pre-incubated with acalabrutinib (ACP) 2 mM, ibrutinib 0.5 mM or dimethylsulfoxide (control) for 1 h at 37°C were perfused through a collagen-coated microcapillary at a physiological arterial shear rate of 1500 s-1 for 180 or 360 s. Surface coverage (%) and thrombi volume (% of vehicle response) were analyzed using ImageJ software. Results are presented as mean ± standard error of mean of three or four independent experiments. *P<0.05, **P<0.01, ***P<0.001 according to two-way analysis of variance (ANOVA) for surface coverage, one-way ANOVA for thrombi volume at 360 s and a one sample t-test for thrombi volume at 180 s.
haematologica | 2019; 104(11)
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