Online publication October 3, 2011 総説特集 : 血栓止血, 凝固線溶 (2) 抗血栓薬の新しい展開新規抗血小板薬の開発要旨 : J Jpn Coll Angiol, 2011, 51: Key words: atherothrombosis

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1 Online publication October 3, 2011 総説特集 : 血栓止血, 凝固線溶 (2) 抗血栓薬の新しい展開新規抗血小板薬の開発要旨 : J Jpn Coll Angiol, 2011, 51: Key words: atherothrombosis, P2Y 12, CYP2C19, GPVI, α IIbβ 3 はじめに 3 atherothrombosis 血小板と動脈硬化 NO / LDL 1 IL-1β CD40L RANTES ApoE GPIbα THE JOURNAL of JAPANESE COLLEGE of ANGIOLOGY Vol. 51 No

2 Figure 1 Molecular mechanisms for arterial thrombus formation (adapted from ref. 3). Platelets adhere to exposed subendothelial matrices, then become activated, change shape, secrete granule content, and aggregate to form thrombi. Critical molecules and proteins involved in these processes are shown. 動脈血栓形成機序 3 Fig von Willebrand factor; VWF VWF 10 µg/ml VWF VWF VWF VWF VWF GPIb-IX-V 3 tethering GPIb-IX VWF α IIbβ 3 GPIIb-IIIa 3 GPIb GPIb α 2β 1 GPVI α 2β 1 GPVI Fc γ 302 脈管学 Vol. 51 No. 3

3 Figure 2 Mechanisms for platelet activation and molecular targets for anti-platelet drugs. Molecular targets for anti-platelet drugs are indicated in italic and bold letters. 2 GPVI Fc γ ADP A 2 TXA 2 G 7 PAR1 PAR4 ADP P2Y 1 P2Y 12 Fig. 2 TXA 2 TXA 2 camp PGI 2 camp α IIbβ 3 camp camp CSPS 2 Cilostazol Stroke Prevention Study P2Y 12 GPVI 1 P2Y 12 ADP ADP in vitro ADP P2Y 1 P2Y 12 P2Y 12 Gαi ADP camp Fig. 3 6 P2Y 12 7 September 25,

4 Figure 3 Platelet ADP receptors (from ref. 6 with modification). Platelets possess at lease two G-protein coupled receptors, P2Y 1 and P2Y 12, as ADP receptors. Figure 4 Impaired platelet aggregation in a patient with P2Y 12 deficiency (from ref. 7 with modification). ADP-induced platelet aggregation was markedly impaired even at high concentrations of ADP. In addition, impaired platelet aggregation was evident in response to low concentrations of collagen and U4419 (TXA 2 analogue) in a patient with P2Y 12 deficiency. Fig. 4 P2Y 12 ADP U46619 TXA 2 ADP P2Y 12 P2Y 12 α IIbβ 3 8 P2Y 12 P2Y 脈管学 Vol. 51 No. 3

5 Figure 5 Classification of P2Y 12 inhibitors. Thienopyridine P2Y 12 inhibitors are prodrugs and irreversibly inhibit P2Y 12, whereas newly developed drugs are active and reversibly inhibit P2Y 12. P450 CYP2C19 CYP2C19 10 P2Y 12 CYP2C19 TRITON-TIMI P2Y 12 P2Y 12 P2Y 12 TicagrelorPLATO 12 CangrelorCHAMPION 13 Fig. 5 PLATO Ticagrelor 16 Cangrelor CHAMPION P2Y 12 2 GPVI GPVI GPVI Fc FcR γ 14 GPVI GPVI GPVI shedding internalize GPVI GPVI GPVI GPVI GPVI GPVI GPVI GPVI 3 PAR1 E5555 September 25,

6 3 VWF α IIbβ 3 α IIbβ 3 α IIbβ 3 α IIbβ 3 3 α IIbβ 3 α IIbβ 3 α IIbβ 3 α IIbβ 3 Abciximab α IIbβ 3 15 α IIbβ 3 α IIbβ 3 α IIbβ 3 α IIbβ 3 α IIbβ 3 おわりに MATCH 16 2 文献 1 Davì G, Patrono C: Platelet activation and atherothrombosis. N Engl J Med 2007; 357: Massberg S, Brand K, Grüner S, et al: A critical role of platelet adhesion in the initiation of atherosclerotic lesion formation. J Exp Med 2002; 196: state of arts Ver , Meadows TA, Bhatt DL: Clinical aspects of platelet inhibitors and thrombus formation. Circ Res 2007; 100: Shinohara Y, Katayama Y, Uchiyama S, et al: Cilostazol for prevention of secondary stroke (CSPS 2): an aspirin-controlled, double-blind, randomised non-inferiority trial. Lancet Neurol 2010; 9: Gachet C: ADP receptors of platelets and their inhibition. Thromb Haemost 2001; 86: Shiraga M, Miyata S, Kato H, et al: Impaired platelet function in a patient with P2Y 12 deficiency caused by a mutation in the translation initiation codon. J Thromb Haemost 2005; 3: Kamae T, Shiraga M, Kashiwagi H, et al: Critical role of ADP interaction with P2Y 12 receptor in the maintenance of α IIbβ 3 activation: association with Rap1B activation. J Thromb Haemost 2006; 4: CAPRIE Steering Committee: A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348: Simon T, Verstuyft C, Mary-Krause M, et al: Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009; 360: Wiviott SD, Braunwald E, McCabe CH, et al: Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357: Wallentin L, Becker RC, Budaj A, et al: Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N 306 脈管学 Vol. 51 No. 3

7 Engl J Med 2009; 361: Harrington RA, Stone GW, McNulty S, et al: Platelet inhibition with cangrelor in patients undergoing PCI. N Engl J Med 2009; 361: GPVI state of arts Ver , Topol EJ, Byzova TV, Plow EF: Platelet GPIIb-IIIa blockers. Lancet 1999; 353: Diener HC, Bogousslavsky J, Brass LM, et al: Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet 2004; 364: Newly Developed Anti-platelet Drugs Yoshiaki Tomiyama Department of Blood Transfusion, Osaka University Hospital, Osaka, Japan Key words: atherothrombosis, P2Y 12, CYP2C19, GPVI, αiibβ3 Platelets play a crucial role in arterial thrombus formation. Atherosclerosis is initially triggered by dysfunctional endothelial cells via inflammatory processes. Recent studies have shown that platelets also play an important role in the initiation of atherosclerotic lesions by releasing inflammatory mediators. Thus, atherosclerosis and thrombosis are interdependent, and these processes are designated as atherothrombosis. As an initial step in thrombogenesis, platelets adhere to altered vascular surfaces or exposed subendothelial matrices. Following adhesion, they become activated, change shape, secrete granule content, and aggregate to form thrombi and provide catalytic surfaces to enhance blood coagulation. A number of adhesive proteins [e.g., von Willebrand factor (VWF), collagen], cell-adhesion receptors (e.g., GPIb-IX, αiibβ3), and platelet receptors (e.g., P2Y 12, GPVI, PAR1) are involved in thrombus formation. This review describes molecular mechanisms for thrombus formation and the targets of newly developed anti-platelet drugs. (J Jpn Coll Angiol, 2011, 51: ) September 25, 2011 Online publication October 3,

Table 1 Isolated venous thrombi in soleal muscle by ultrasonography US finding Acute Chronic Total No. Early stage non-retracted slightl

Table 1 Isolated venous thrombi in soleal muscle by ultrasonography US finding Acute Chronic Total No. Early stage non-retracted slightl Online publication October 8, 2010 原著第 50 回総会座長推薦論文孤立性ひらめ筋内静脈血栓と抗核抗体との関連 1 2 要旨 : 89 116 D 3 30 70 63 26 100 J Jpn Coll Angiol, 2010, 50: 417 422 Key words: isolated soleal venous thrombi, recurrent

Online publication October 3, 2011 総 説 特集 : 血栓止血, 凝固線溶 (2) 抗血栓薬の新しい展開 新規抗血小板薬の開発 要旨 : J Jpn Coll Angiol, 2011, 51: Key words: atherothrombosis

Online publication October 3, 2011 総説特集 : 血栓止血, 凝固線溶 (2) 抗血栓薬の新しい展開新規抗血小板薬の開発要旨 : J Jpn Coll Angiol, 2011, 51: Key words: atherothrombosis