High Prevalence of Platelet Dysfunction Among Patients with Chronic Myeloid Leukemia Receiving Tyrosine Kinase Inhibitors
Authors: Warit Wangsuekul , Norasetthada Lalita , Tantiworawit Adisak , Rattarittamrong Ekarat , Chai-adisaksopha Chatree , Hantrakool Sasinee , Ornkamon Wongtagan , Nawarawong Weerasak 
Published: October 2019

Abstract
BACKGROUND - Tyrosine kinase inhibitors (TKIs) have become a standard of care for chronic myeloid leukemia (CML) with the favorable safety profile. However, there were few reports regarding TKIs induced platelet dysfunction, which might be contributed to bleeding complication. Therefore, we aimed to examine the prevalence and pattern of platelet function abnormalities responding to different agonists among patients with CML receiving TKIs.
METHODS - This is a descriptive cross-sectional study. Patients with CML at any phases, either on TKIs or treatment-naïve, were included. Patients with known cause of platelet dysfunction or thrombocytopenia were excluded. We tested platelet aggregation on stimulation by 4 agonists, including 2.5 and 20-mmol/L ADP, 10-mmol/L epinephrine, 2-mg/mL collagen and 1-mmol/L arachidonic acid. Significant platelet dysfunction was defined as less than 60% of platelet aggregation upon stimulation by at least 2 agonists.
RESULT - There were 78 patients with CML either treatment naïve (n=5) or receiving imatinib (n= 56), nilotinib (n = 15) or dasatinib (n = 2). Most of patients (n = 69) were in chronic phase while there were 2 and 3 patients were in accelerated and blastic phase, respectively. Majority of patients achieved at least complete cytogenetic response (86.4%). Prevalence of significant platelet dysfunction among patients with CML receiving imatinib, nilotinib, dasatinib and treatment-naïve were 77%, 60%, 50% and 20%, respectively (p < .0001). Impaired platelet aggregation (aggregation < 60%) on stimulation with arachidonic acid, collagen and epinephrine was observed in 80%, 68%, and 52% of patients on imatinib, meanwhile, the corresponding figures for patients on nilotinib were 33%, 53% and 47%, respectively. All TKIs seemed to have the same pattern of impaired platelet aggregation on stimulation by arachidonic acid, collagen and epinephrine; however, the proportion of patients with impaired platelet aggregation responding to arachidonic acid was more prominent in imatinib group (p < .0001). Mean maximal amplitude of platelet aggregation on stimulation by arachidonic acid in treatment-naïve, imatinib, nilotinib and dasatinib were 77.4%, 33.4%, 58.2% and 61.0%, respectively (p < .0001) (Figure 1). While mean maximal amplitude of platelet aggregation responding to collagen in treatment-naïve, imatinib, nilotinib and dasatinib were 78.4%, 39.9%, 46.2% and 66.0%, respectively (p = .001) (Figure 2).
CONCLUSION - High prevalence of platelet dysfunction has been demonstrated in CML patients receiving all types of TKIs including imatinib. The cause of platelet dysfunction is likely to be from TKIs more than intrinsic platelet dysfunction from CML itself as majority of treatment-naïve patients had normal platelet function. The risk of bleeding in patients taking TKIs should be concerned in particularly those receiving concomitant antiplatelet medications or undergoing invasive procedures.
Figure 1. Percentage of platelet aggregation responding to arachidonic acid according to CML treatment Figure 1. Percentage of platelet aggregation responding to arachidonic acid according to CML treatment
Figure 2. Percentage of platelet aggregation responding to collagen according to CML treatment Figure 2. Percentage of platelet aggregation responding to collagen according to CML treatment

Disclosures
No relevant conflicts of interest to declare.