Key Points• Ibrutinib affects collagen and VWF-mediated platelet activation.• The bleeding diathesis correlates with defects in collagen-induced platelet aggregation and firm adhesion on VWF at arterial shear rate.The oral Bruton's tyrosine kinase inhibitor, ibrutinib, has recently demonstrated high efficiency in patients with relapsed B-cell malignancies. Occurrence of bleeding events has been reported in a subgroup of ibrutinib-treated patients. We demonstrate that ibrutinib selectively inhibits platelet signaling and functions downstream of the collagen receptor glycoprotein VI and strongly affects firm platelet adhesion on von Willebrand factor (VWF) under arterial flow. A longitudinal study of 14 patients indicated a correlation between occurrence of bleeding events and decreased platelet aggregation in response to collagen in platelet-rich plasma and firm adhesion on VWF under arterial flow. The addition of 50% untreated platelets was sufficient to efficiently reverse the effects of ibrutinib, and platelet functions recovered after treatment interruption as physiological platelet renewal occurred. These data have important clinical implications and provide a basis for hemostasis management during ibrutinib treatment. (Blood. 2014;124(26):3991-3995)
IntroductionThe Bruton tyrosine kinase (Btk) is an essential actor downstream of the B-cell receptor, and its covalent inhibitor, ibrutinib, has recently been approved for therapies of relapsed chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). [1][2][3][4][5][6][7][8] Bleeding has been reported in up to 50% of ibrutinib-treated patients. Most events were grade 1 to 2 (spontaneous bruising or petechiae), but in 5% of patients, they were of grade 3 or higher after trauma. [4][5][6] Platelets are the most important blood cells to prevent bleeding after vascular injury. Two Tec family kinases, Btk and Tec, are involved in platelet activation downstream of the collagen receptor glycoprotein VI (GPVI) via phospholipase Cg2 (PLCg2) phosphorylation and activation.9,10 Under arterial shear rate, interaction of platelets with the damaged vessel wall is largely mediated by binding of von Willebrand factor (VWF) to its receptor, the GPIb-IX-V complex. In a mouse model, Btk has been shown to play a role in VWF/GPIb-IX-V-induced platelet activation.11 To further characterize the bleeding events in ibrutinib-treated patients, we investigated the effect of this drug on platelet functions in vitro and ex vivo in 14 patients.
Study designFor in vitro experiments, whole blood, platelet-rich plasma (PRP), or washed platelets from healthy donors free of antiplatelet medication were preincubated with ibrutinib (PCI-32765; Selleckchem) or dimethylsulfoxide for 10 or 30 minutes as indicated. For ex vivo experiments, blood samples were obtained before and 2 to 4 weeks after starting ibrutinib treatment (Imbruvica; Janssen-Cilaq Laboratories) in patients with CLL (420 mg daily) or MCL (560 mg daily) [4][5][6] (French compassionate use program) after informed consent, in ...
Change blindness -our inability to detect changes in a stimulus -occurs even when the change takes place gradually, without disruption (Simons, Franconeri, & Reimer, 2000). Such gradual changes are more difficult to detect than changes that involve a disruption. In this experiment, we extend previous findings to the domain of facial expressions of emotions occurring in the context of a realistic scene. Even with changes occurring in central, highly relevant stimuli such as faces, gradual changes still produced high levels of change blindness: Detection rates were three times lower for gradual changes than for displays involving disruption, with only 15% of the observers perceiving the gradual change within a single trial. However, despite this high rate of change blindness, changes on faces were significantly better detected than colour changes occurring on non facial objects in the same scene.
In a population with abnormal FHR in labor, STAN sensitivity is moderate (almost 40%) for predicting pH< or =7.15 and better (almost 60%) for more severe acidosis (pH< or =7.05).
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