TY - JOUR
T1 - Doxorubicin-induced platelet procoagulant activities
T2 - An important clue for chemotherapy-associated thrombosis
AU - Kim, Se Hwan
AU - Lim, Kyung Min
AU - Noh, Ji Yoon
AU - Kim, Keunyoung
AU - Kang, Seojin
AU - Chang, Youn Kyeong
AU - Shin, Sue
AU - Chung, Jin Ho
N1 - Funding Information:
National Research Foundation of Korea grant funded by the Korean government (MEST) (20100001707).
PY - 2011/11
Y1 - 2011/11
N2 - Thrombotic risk associated with chemotherapy including doxorubicin (DOX) has been frequently reported; yet, the exact mechanism is not fully understood. Here, we report that DOX can induce procoagulant activity in platelets, an important contributor to thrombus formation. In human platelets, DOX increased phosphatidylserine (PS) exposure and PS-bearing microparticle (MP) generation. Consistently, DOX-treated platelets and generated MPs induced thrombin generation, a representative marker for procoagulant activity. DOX-induced PS exposure appeared to be from intracellular Ca 2+ increase and ATP depletion, which resulted in the activation of scramblase and inhibition of flippase. Along with this, apoptosis was induced by DOX as determined by the dissipation of mitochondrial membrane potential (Δψ), cytochrome c release, Bax translocation, and caspase-3 activation. A Ca 2+ chelator ethylene glycol tetraacetic acid, caspase inhibitor Q-VD-OPh, and antioxidants (vitamin C and trolox) can attenuate DOX-induced PS exposure and procoagulant activity significantly, suggesting that Ca 2+, apoptosis, and reactive oxygen species (ROS) were involved in DOX-enhanced procoagulant activity. Importantly, rat in vivo thrombosis model demonstrated that DOX could manifest prothrombotic effects through the mediation of platelet procoagulant activity, which was accompanied by increased PS exposure and Δψ dissipation in platelets.
AB - Thrombotic risk associated with chemotherapy including doxorubicin (DOX) has been frequently reported; yet, the exact mechanism is not fully understood. Here, we report that DOX can induce procoagulant activity in platelets, an important contributor to thrombus formation. In human platelets, DOX increased phosphatidylserine (PS) exposure and PS-bearing microparticle (MP) generation. Consistently, DOX-treated platelets and generated MPs induced thrombin generation, a representative marker for procoagulant activity. DOX-induced PS exposure appeared to be from intracellular Ca 2+ increase and ATP depletion, which resulted in the activation of scramblase and inhibition of flippase. Along with this, apoptosis was induced by DOX as determined by the dissipation of mitochondrial membrane potential (Δψ), cytochrome c release, Bax translocation, and caspase-3 activation. A Ca 2+ chelator ethylene glycol tetraacetic acid, caspase inhibitor Q-VD-OPh, and antioxidants (vitamin C and trolox) can attenuate DOX-induced PS exposure and procoagulant activity significantly, suggesting that Ca 2+, apoptosis, and reactive oxygen species (ROS) were involved in DOX-enhanced procoagulant activity. Importantly, rat in vivo thrombosis model demonstrated that DOX could manifest prothrombotic effects through the mediation of platelet procoagulant activity, which was accompanied by increased PS exposure and Δψ dissipation in platelets.
KW - Doxorubicin
KW - Platelets
KW - PS exposure
KW - Thrombosis
UR - http://www.scopus.com/inward/record.url?scp=84155175860&partnerID=8YFLogxK
U2 - 10.1093/toxsci/kfr222
DO - 10.1093/toxsci/kfr222
M3 - Article
C2 - 21865289
AN - SCOPUS:84155175860
SN - 1096-6080
VL - 124
SP - 215
EP - 224
JO - Toxicological Sciences
JF - Toxicological Sciences
IS - 1
M1 - kfr222
ER -