Anticoagulants of primary haemostasis

J. Kössler; U. Steigerwald; U. Walter

doi:10.1055/s-0037-1617031

Hämostaseologie, Table of Contents

Hamostaseologie 2009; 29(03): 274-278
DOI: 10.1055/s-0037-1617031

Review

Schattauer GmbH

Anticoagulants of primary haemostasis

Antikoagulanzien der primären Hämostase

J. Kössler

¹Institut für Klinische Biochemie und Pathobiochemie, Zentrallabor mit Gerinnungsambulanz, Universitätsklinikum Würzburg

,

U. Steigerwald

¹Institut für Klinische Biochemie und Pathobiochemie, Zentrallabor mit Gerinnungsambulanz, Universitätsklinikum Würzburg

,

U. Walter

¹Institut für Klinische Biochemie und Pathobiochemie, Zentrallabor mit Gerinnungsambulanz, Universitätsklinikum Würzburg

› Author Affiliations

Abstract

Summary

Inhibition of platelet function plays an important role in the treatment and secondary prevention of cardiovascular or cerebrovascular ischemic diseases. Established antiplatelet agents use different pharmacological targets for this role. Acetylic salicylic acid achieves a reduction of thromboxane A2 formation by inhibition of COX-1. Ticlopidin or clopidogrel are ADP-P2Y₁₂ receptor antagonists. Tirofiban, abciximab or eptifibatid are used for the inhibition of the glycoprotein IIb/IIIa receptor which is activated at the surface of platelets preceding the final step of their aggregation. The mechanism of dipyridamole is based on the inhibition of adenosine uptake and of phosphodiesterase-5.

Efforts are made to improve antiplatetelet therapy with the aim to find agents with favorable clinical outcome and lower bleeding risk. Current clinical studies focus on a new generation of ADP receptor antagonists (prasugrel, cangrelor and ticagrelor) as successors of ticlopidin and clopidogrel after coronary arterial interventions. Developments using platelet targets different from established drugs are thrombin receptor antagonists (like SCH530348) or thromboxane receptor antagonists (like S18886/terutroban) in patients with cerebrovascular events. Results from recent experimental studies could lead to new strategies for antiplatetelet therapy (like inhibition of GP Ib receptor, GP VI receptor, platelet-leukocyte interaction, factor XII and others) in the future.

Zusammenfassung

Die Hemmung der Thrombozytenfunktion spielt eine wichtige Rolle bei der Behandlung und Sekundärprophylaxe von kardio- oder zerebrovaskulären ischämischen Erkrankungen. Etablierte plättchenhemmende Medikamente sind gegen unterschiedliche pharmakologische Angriffspunkte gerichtet. Acetylsalicylsäure bewirkt eine Reduktion der Thromboxan-A2-Produktion durch Blockade der COX-1. Ticlopidin oder Clopidogrel sind ADPP2Y₁₂-Rezeptorantagonisten. Tirofiban, Abciximab oder Eptifibatid werden zur Hemmung der Glykoprotein-IIb/IIIa-Rezeptoren eingesetzt, die in der letzten Stufe der Thrombozytenaktivierung auf der Thrombozytenoberfläche aktiviert werden. Die Wirkung von Dipyridamol geht auf die Aufnahmehemmung von Adenosin und Hemmung der Phosphodiesterase-5 zurück.

Die Verbesserungen in der plättchenhemmenden Therapie verfolgen das Ziel, Substanzen zu finden, die bessere klinische Ergebnisse bei geringerem Blutungsrisiko aufweisen. Studien konzentrieren sich zurzeit auf eine neue Generation der ADP-Rezeptor-Antagonisten (Prasugrel, Cangrelor, Ticagrelor) als Nachfolger von Ticlopidin und Clopidogrel zur Therapie nach Koronarinterventionen. Entwicklungen, die im Vergleich zu den etablierten Medikamenten neue thrombozytäre Angriffspunkte verwenden, sind Thrombin-Rezeptorantagonisten (wie SCH530348) oder ThromboxanRezeptorantagonisten (wie S18886 bzw. Terutroban) bei Patienten nach zerebrovaskulären Ereignissen. Experimentelle Studien könnten zu neuen Strategien der plättchenhemmenden Medikation (Hemmung der GP-Ib-Rezeptor, GP-VI-Rezeptor, Thrombozyten-Leukozyten-Interaktion, Faktor XII) führen.

Keywords

Antiplatelet agent - acetylic salicylic acid - ADP receptor antagonist - secondary prevention

Schlüsselwörter

Thrombozytenaggregationshemmer - Acetylsalicylsäure - ADP-Rezeptorantagonist - Sekundär -prävention

Full Text

References

Literatur
1 Adams HP, Effron MB, Torner J. et al. Emergency administration of abciximab for treatment of patients with acute ischemic stroke: Results of an international phase III trial: Abciximab in Emergency Treatment of Stroke Trial (AbESTT-II). Stroke 2008; 39: 87-99.
2 Adams RJ, Albers G, Alberts MJ. Update to the AHA/ASA recommendations for the prevention of stroke in patients with stroke and transient ischemic attack. Stroke 2008; 39: 1647-1652.
3 Ajzenberg N, Aubry P, Huisse MG. et al. Enhanced shear-induced platelet aggregation in patients who experience subacute stent thrombosis: a case-control study. J Am Coll Cardiol 2005; 45: 1753-1756.
4 Aktas B, Utz A, Hoenig-Lidl P. et al. Dipyridamole enhances NO/cGMP-mediated vasodilator-stimulated phosphoprotein phosphorylation and signaling in human platelets. Stroke 2003; 34: 764-769.
5 Anderson JL, Adams CD, Antman EM. et al. ACC/ AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction. J Am Coll Cardiol 2007; 50: e1-e157.
6 Anderson JL, Adams CD, Antmann EM. et al. ACC/ AHA 2007 guidelines for the management of patients with unstable angina/non ST-Elevation myocardial infarction. Circulation 2007; 116: e148-e304.
7 Angiolillo DJ, Bates ER, Bass TA. Clinical profile of prasugrel, a novel thienopyridine. Am Heart J 2008; 156: 16-22.
8 Angiolillo DJ, Capranzano P. Pharmacology of emerging novel platelet inhibitors. Am Heart J 2008; 156: 10-15.
9 Angiolillo D, Guzman LA. Clinical overview of promising nonthienopyridine antiplatelet agents. Am Heart J 2008; 156: 23-28.
10 Antithrombotic Trialists’ Collaboration.. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. Br Med J 2002; 324: 71-86.
11 Antmann EM, Hand M, Armstrong PW. et al. 2007 focused update of the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction. Circulation 2008; 117: 296-329.
12 Barragan P, Bouvier JL, Roquebert PO. et al. Resistance to thienopyridines: Clinical detection of coronary stent thrombosis by monitoring of vasodilator-stimulated phosphoprotein phosphorylation. Catheter Cardiovasc Interv 2003; 59: 295-302.
13 Bassand JP, Hamm CW, Ardissino D. et al. Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes. Eur Heart J 2007; 28: 1598-1660.
14 Bertrand ME, Rupprecht HJ, Urban P. et al. Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting: the Clopidogrel Aspirin Stent International Cooperative Study (CLASSICS). Circulation 2000; 102: 624-629.
15 Bonello L, Camoin-Jau L, Arques S. et al. Adjusted clopidogrel loading doses according to vasodilator-stimulated phosphoprotein phosphorylation index decrease rate of major adverse cardiovascular events in patients with clopidogrel resistance: a multicenter randomized prospective study. J Am Coll Cardiol 2008; 51: 1404-1411.
16 Bonello L, Paganelli F, Arpin-Bornet M. et al. Vasodilator-stimulated phosphoprotein phosphorylation analysis prior to percutaneous coronary intervention for exclusion of postprocedural major adverse cardiovascular events. J Thromb Haemost 2007; 5: 1630-1636.
17 Born G, Patrono C. Antiplatelet drugs. Br J Pharmacol 2006; 147: 241-251.
18 Botting RM. Inhibitors of cyclooxygenases: Mechanisms, selectivity and uses. J Physiol Pharmacol 2006; 57: 113-124.
19 Brandt JT, Payne CD, Wiviott SD. et al. A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation. Am Heart J 2007; 153: 66e9-16.
20 CAPRIE Steering Committee.. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348: 1329-1339.
21 Chew DP, Bhatt DL, Sapp S. et al. Increased mortality with oral platelet glycoprotein IIb/IIIa antagonists: a meta-analysis of phase III multicenter randomized trials. Circulation 2001; 103: 201-206.
22 Cuisset T, Frere C, Quilici J. et al. High post-treatment platelet reactivity identified low-responders to dual antiplatelet therapy at increased risk of recurrent cardiovascular events after stenting for acute coronary syndrome. J Thromb Haemost 2006; 4: 542-549.
23 Cuisset T, Frere C, Quilici J. et al. Benefit of a 67031-mg loading dose of clopidogrel on platelet reactivity and clinical outcomes in patients with non-ST-segment elevation acute coronary syndrome undergoing coronary stenting. J Am Coll Cardiol 2006; 48: 1339-1345.
24 De Meyer SF, Vanhoorelbeke K, Broos K. et al. Anti-platelet drugs. Br J Haematol 2008; 142: 515-528.
25 De Miguel A, Ibanez B, Badimon JJ. Clinical implications of clopidogrel resistance. Thromb Haemost 2008; 100: 196-203.
26 De Schryver E, Algra A, van Gijn J. Dipyridamole for preventing stroke and other vascular events in patients with vascular disease. Cochrane Database Syst Rev 2006; 2: CD001820.
27 De Schryver E, Algra A, van Gijn J. Dipyridamole for preventing stroke and other vascular events in patients with vascular disease. An update. Stroke 2008; 39: 1397-1398.
28 Diener H, Cunha L, Forbes C. et al. European Stroke Prevention Study: II. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci 1996; 143: 1-13.
29 Diener HC. Primär- und Sekundärprävention der zerebralen Ischämie. www.dgn.org/Leitlinien.
30 ESPRIT Study Group.. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT). Lancet 2006; 367: 1665-1673.
31 Furie B, Furie BC. Mechanisms of thrombus formation. N Engl J Med 2008; 359: 938-949.
32 Gachet C. P2 receptors, platelet function and pharmacological implications. Thromb Haemost 2008; 99: 466-472.
33 Gasparyan AY, Watson T, Lip G. The role of aspirin in cardiovascular prevention. J Am Coll Cardiol 2008; 51: 1829-1843.
34 Geiger J, Teichmann L, Grossmann R. et al. Monitoring of clopidogrel action: Comparison of methods. Clin Chem 2005; 51: 957-965.
35 Graham I, Atar D, Borch-Johnsen K. et al. European guidelines on cardiovascular disease prevention in clinical practice. Eur J Cardiovasc Prev Rehabil 2007; 14: 1-113.
36 Gurbel PA, Bliden KP, Hiatt BL. et al. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation 2003; 107: 2908-2913.
37 Gurbel PA, Tantry US. Aspirin and clopidogrel resistance: consideration and management. J Interv Cardiol 2006; 19: 439-448.
38 Gurbel PA, Bliden KP, Samara W. et al. Clopidogrel effect on platelet reactivity in patients with stent thrombosis: results of the CREST Study. J Am Coll Cardiol 2005; 46: 1827-1832.
39 Hirsch AT, Haskal ZJ, Hertzer NR. ACC/AHA 2005 practice guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic). Circulation 2006; 113: e463-e654.
40 Kleinschnitz C, Pozgajova M, Pham M. et al. Targeting platelets in acute experimental stroke: impact of glycoprotein Ib, VI, IIb/IIIa blockade on infarct size, functional outcome and intracranial bleeding. Circulation 2007; 115: 2323-2330.
41 Kroetz F, Sohn HY, Klauss V. Antiplatelet drugs in cardiological practice: Established strategies and new developments. Vasc Health and Risk Manag 2008; 4: 637-645.
42 Lubbe DF, Berger PB. The thienopyridines. J Interv Cardiol 2002; 15: 85-93.
43 Mehta SR, Yusuf S, Peters RJ. et al. Effects of pre-treatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001; 358: 527-533.
44 Mukherjee D, Roffi M. Glycoprotein IIb/IIIa receptor inhibitors in 2008: Do they still have a role?. J Interven Cardiol 2008; 21: 118-121.
45 O’Donnell MJ, Hankey GJ, Eikelboom JW. Antiplatelet therapy for secondary prevention of non -cardioembolic ischemic stroke: A critical review. Stroke 2008; 39: 1638-1646.
46 Rosamond W, Flegal K, Furie K. et al. Heart disease and stroke statistics 2008 update. Circulation 2008; 117: e25-e146.
47 Rothwell PM, Coull AJ, Silver LE. et al. Oxford Vascular Study. Population-based study of event-rate, incidence, case fatality, and mortality for all acute vascular events in all arterial territories. Lancet 2005; 366: 1773-1783.
48 Ruggeri ZM. Platelets in atherothrombosis. Nat Med 2002; 8: 1227-1234.
49 Savi P, Herbert JM. Clopidogrel and ticlopidine: P2Y₁₂ adenosine diphosphate-receptor antagonists for the prevention of atherothrombosis. Semin Thromb Hemost 2005; 31: 174-183.
50 Silber S, Albertsson P, Aviles FF. et al. Guidelines for percutaneous coronary interventions. Eur Heart J 2005; 26: 804-847.
51 Smith Jr SC, Feldman TE, Hirshfeld Jr JW. et al. ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention. Circulation 2006; 113: e166-e286.
52 Smyth SS, Woulfe DS, Weitz JI. et al. G-Protein-coupled receptors as signaling targets for antiplatelet therapy. Arterioscler Thromb Vasc Biol 2009; 29: 449-457.
53 Stoll G, Kleinschnitz C, Nieswandt B. Molecular mechanisms of thrombus formation in ischemic stroke: novel insights and targets for treatment. Blood 2008; 112: 3555-3562.
54 Yusuf S, Zhao F, Mehta SR. et al. Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001; 345: 494-502.