Emergence of a Ph-negative Clone in a Child With Ph+ ALL

Mehrhoff, Casey J; Hemenway, Charles S.; Suh, Eugene

doi:10.1097/mph.0000000000001521

Cited by 2 publications

(1 citation statement)

References 15 publications

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“…Patients with Ph+ adult acute lymphoblastic leukemia (ALL) may also benefit from an alternate TKI therapy [3]. In the treatment of pediatric patients with Ph+ ALL the addition of TKIs to conventional chemotherapy has improved outcomes of patients [4]. It has long been known that second-generation TKIs may have side effects as nilotinib can potentiate a prothrombotic state [5] while dasatinib is known to cause platelet dysfunction e.g.…”

Section: Introductionmentioning

confidence: 99%

Dasatinib Inhibits Procoagulant and Clot Retracting Activities of Human Platelets

Debreceni

Mezei

Batár

et al. 2019

IJMS

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Tyrosine kinase inhibitors (TKI) such as the BCR-ABL inhibitor dasatinib and nilotinib are highly effective therapies for chronic myeloid leukemia (CML). However, several lines of evidence suggest that dasatinib can induce bleeding which may be due to impaired collagen-induced platelet adhesion, aggregation, and secretion. Sarcoma family kinases (SFK) play central role in the GPVI-induced signaling pathway. We aimed to investigate whether and how dasatinib can modulate SFK-mediated platelet procoagulant activity in a purified system and in dasatinib/nilotinib treated CML patients. In platelet rich plasmas of healthy volunteers, dasatinib dose-dependently reduced convulxin-induced phosphatidylserine exposure and attenuated thrombin formation. Similarly to these changes, integrin activation and clot retraction were also significantly inhibited by 100 nM dasatinib. Platelets isolated from dasatinib treated patients showed a significantly lower phosphatidylserine expression upon convulxin activation compared to premedication levels. In these samples, thrombin generation was significantly slower, and the quantity of formed thrombin was less compared to the trough sample. Western blot analyses showed decreased phosphorylation levels of the C-terminal tail and the activation loop of SFKs upon dasatinib administration. Taken together, these results suggest that dasatinib inhibits the formation of procoagulant platelets via the GPVI receptor by inhibiting phosphorylation of SFKs.

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Section: Introductionmentioning

confidence: 99%