title: Doxorubicin-induced platelet procoagulant activities: an important clue for chemotherapy-associated thrombosis.
abstract: 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 Ca²⁺ 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 Ca²⁺ 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 Ca²⁺, 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.
authors.affiliation: College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
authors.forename: Se-Hwan
authors.initials: SH
authors.lastname: Kim
authors.forename: Kyung-Min
authors.initials: KM
authors.lastname: Lim
authors.forename: Ji-Yoon
authors.initials: JY
authors.lastname: Noh
authors.forename: Keunyoung
authors.initials: K
authors.lastname: Kim
authors.forename: Seojin
authors.initials: S
authors.lastname: Kang
authors.forename: Youn Kyeong
authors.initials: YK
authors.lastname: Chang
authors.forename: Sue
authors.initials: S
authors.lastname: Shin
authors.forename: Jin-Ho
authors.initials: JH
authors.lastname: Chung
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects* / Q000627:therapeutic use; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000009:adverse effects* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D018613:Microscopy, Confocal; D015539:Platelet Activation / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects*; D021381:Protein Transport; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013927:Thrombosis / Q000097:blood / Q000139:chemically induced*; D013997:Time Factors; D055815:Young Adult; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; C494826:BAX protein, human; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; D004317:Doxorubicin; D045304:Cytochromes c; D053148:Caspase 3