Future Antithrombotic Therapies in Cardiology

Abstract

Thrombi are composed of activated platelets and fibrin, the latter being the final product of the blood coagulation system. Therefore, antithrombotic therapies may either interfere with adhesion, aggregation, secretion or signalling of platelets or with fibrin formation. Established drugs potently inhibit clot formation, but also increase the risk of bleeding. In this review article, we discuss novel strategies for the inhibition of pathological thrombosis while enabling normal haemostasis, thus minimizing the risk of bleeding.

Zusammenfassung

Blutgerinnsel setzen sich aus aktivierten Blutplättchen und Fibrin zusammen, wobei letzteres als Endprodukt aus der Blutgerinnungskaskade hervorgeht. Antithrombotische Therapien setzen daher an der Adhäsion, Aggregation, Sekretion und Signalvermittlung von Plättchen oder an der Fibrinbildung an. Die etablierten Medikamente verhindern zwar die Gerinnselbildung, sie erhöhen aber das Blutungsrisiko. In diesem Übersichtsartikel beschreiben wir daher neuartige Ansätze, um pathologische Thrombenbildung zu hemmen unter Beibehaltung normaler Hämostase und damit Minimierung des Blutungsrisikos.

Keywords

thrombus - platelets - therapy

Schlüsselworte

Blutgerinnsel - Blutplättchen - Therapie

• References

• 1 Wendelboe AM, Raskob GE. Global burden of thrombosis: epidemiologic aspects. Circ Res 2016; 118 (09) 1340-1347
• 2 Jackson SP. Arterial thrombosis--insidious, unpredictable and deadly. Nat Med 2011; 17 (11) 1423-1436
• 3 White RH. The epidemiology of venous thromboembolism. Circulation 2003; 107 (23) (Suppl. 01) I4-I8
• 4 Xu XR, Carrim N, Neves MAD. , et al. Platelets and platelet adhesion molecules: novel mechanisms of thrombosis and anti-thrombotic therapies. Thromb J 2016; 14 (Suppl. 01) 29
• 5 Ruggeri ZM. Platelets in atherothrombosis. Nat Med 2002; 8 (11) 1227-1234
• 6 Saito H, Matsushita T, Kojima T. Historical perspective and future direction of coagulation research. J Thromb Haemost 2011; 9 (Suppl. 01) 352-363
• 7 Smith SA, Choi SH, Davis-Harrison R. , et al. Polyphosphate exerts differential effects on blood clotting, depending on polymer size. Blood 2010; 116 (20) 4353-4359
• 8 Long AT, Kenne E, Jung R, Fuchs TA, Renné T. Contact system revisited: an interface between inflammation, coagulation, and innate immunity. J Thromb Haemost 2016; 14 (03) 427-437
• 9 Ferreiro JL, Angiolillo DJ. New directions in antiplatelet therapy. Circ Cardiovasc Interv 2012; 5 (03) 433-445
• 10 Weitz JI, Harenberg J. New developments in anticoagulants: past, present and future. Thromb Haemost 2017; 117 (07) 1283-1288
• 11 Levine M, Goldstein JN. Bleeding complications of targeted oral anticoagulants: what is the risk?. Hematology (Am Soc Hematol Educ Program) 2014; 2014 (01) 504-509
• 12 McFadyen JD, Schaff M, Peter K. Current and future antiplatelet therapies: emphasis on preserving haemostasis. Nat Rev Cardiol 2018; 15 (03) 181-191
• 13 Eggers AE. A hypothesis about how to achieve anticoagulation without bleeding. Med Hypotheses 2015; 85 (06) 720-722
• 14 Ovanesov MV, Ananyeva NM, Panteleev MA, Ataullakhanov FI, Saenko EL. Initiation and propagation of coagulation from tissue factor-bearing cell monolayers to plasma: initiator cells do not regulate spatial growth rate. J Thromb Haemost 2005; 3 (02) 321-331
• 15 Larsson M, Rayzman V, Nolte MW. , et al. A factor XIIa inhibitory antibody provides thromboprotection in extracorporeal circulation without increasing bleeding risk. Sci Transl Med 2014; 6 (222) 222ra17
• 16 McFadyen JD, Peter K. Novel antithrombotic drugs on the horizon: the ultimate promise to prevent clotting while avoiding bleeding. Circ Res 2017; 121 (10) 1133-1135
• 17 Preis M, Hirsch J, Kotler A. , et al. Factor XI deficiency is associated with lower risk for cardiovascular and venous thromboembolism events. Blood 2017; 129 (09) 1210-1215
• 18 Duga S, Salomon O. Factor XI deficiency. Semin Thromb Hemost 2009; 35 (04) 416-425
• 19 Büller HR, Bethune C, Bhanot S. , et al; FXI-ASO TKA Investigators. Factor XI antisense oligonucleotide for prevention of venous thrombosis. N Engl J Med 2015; 372 (03) 232-240
• 20 Wiviott SD, Braunwald E, McCabe CH. , et al; TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357 (20) 2001-2015
• 21 Wallentin L, Becker RC, Budaj A. , et al; PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361 (11) 1045-1057
• 22 Mojica Muñoz A-K, Jamasbi J, Uhland K. , et al. Recombinant GPVI-Fc added to single or dual antiplatelet therapy in vitro prevents plaque-induced platelet thrombus formation. Thromb Haemost 2017; 117 (08) 1651-1659
• 23 Dütting S, Bender M, Nieswandt B. Platelet GPVI: a target for antithrombotic therapy?!. Trends Pharmacol Sci 2012; 33 (11) 583-590
• 24 Kato K, Kanaji T, Russell S. , et al. The contribution of glycoprotein VI to stable platelet adhesion and thrombus formation illustrated by targeted gene deletion. Blood 2003; 102 (05) 1701-1707
• 25 Arthur JF, Dunkley S, Andrews RK. Platelet glycoprotein VI-related clinical defects. Br J Haematol 2007; 139 (03) 363-372
• 26 Jamasbi J, Megens RTA, Bianchini M. , et al. Differential inhibition of human atherosclerotic plaque-induced platelet activation by dimeric GPVI-Fc and anti-GPVI antibodies: functional and imaging studies. J Am Coll Cardiol 2015; 65 (22) 2404-2415
• 27 Ungerer M, Rosport K, Bültmann A. , et al. Novel antiplatelet drug revacept (Dimeric Glycoprotein VI-Fc) specifically and efficiently inhibited collagen-induced platelet aggregation without affecting general hemostasis in humans. Circulation 2011; 123 (17) 1891-1899
• 28 Hohmann JD, Wang X, Krajewski S. , et al. Delayed targeting of CD39 to activated platelet GPIIb/IIIa via a single-chain antibody: breaking the link between antithrombotic potency and bleeding?. Blood 2013; 121 (16) 3067-3075
• 29 Assinger A, Laky M, Schabbauer G. , et al. Efficient phagocytosis of periodontopathogens by neutrophils requires plasma factors, platelets and TLR2. J Thromb Haemost 2011; 9 (04) 799-809
• 30 Gaertner F, Massberg S. Blood coagulation in immunothrombosis - at the frontline of intravascular immunity. Semin Immunol 2016; 28 (06) 561-569
• 31 Gaertner F, Ahmad Z, Rosenberger G. , et al. Migrating platelets are mechano-scavengers that collect and bundle bacteria. Cell 2017; 171 (06) 1368-1382.e23
• 32 Zhou X, Liu X-L, Ji W-J. , et al. The kinetics of circulating monocyte subsets and monocyte-platelet aggregates in the acute phase of ST-elevation myocardial infarction: associations with 2-year cardiovascular events. Medicine (Baltimore) 2016; 95 (18) e3466
• 33 Wang Y, Gao H, Shi C. , et al. Leukocyte integrin Mac-1 regulates thrombosis via interaction with platelet GPIbα. Nat Commun 2017; 8: 15559
• 34 Angiolillo DJ, Goodman SG, Bhatt DL. , et al. Antithrombotic therapy in patients with atrial fibrillation undergoing percutaneous coronary intervention: a North American perspective-2016 update. Circ Cardiovasc Interv 2016; 9 (11) e004395