Management of bleeding in patients using antithrombotic agents

R. E. Scharf

doi:10.1055/s-0037-1617135

Hämostaseologie, Table of Contents

Hamostaseologie 2009; 29(04): 388-398
DOI: 10.1055/s-0037-1617135

Review

Schattauer GmbH

Management of bleeding in patients using antithrombotic agents

Prediction, prevention, protection and problem-oriented interventionBehandlung von Patienten mit Blutungen unter antithrombotischer TherapiePrädiktion, Prävention, Protektion, problemorientierte Intervention

Authors

R. E. Scharf

¹Institut für Experimentelle und Klinische Hämostaseologie, Hämotherapie und Transfusionsmedizin, Universitäts -klinikum Düsseldorf, und Biologisch-Medizinisches Forschungszentrum der Heinrich-Heine-Universität Düsseldorf

Abstract

Summary

Antiplatelet agents and anticoagulants are effective in the prevention and treatment of a variety of thrombotic disorders. Several clinical settings require more intense antithrombotic regimens. These can be provided by combining (i) two antiplatelet drugs, (ii) anti-platelet monotherapy with an anticoagulant, or (iii) anticoagulation with dual antiplatelet treatment (triple therapy). A major side effect of all antithrombotic regimens, however, is the induction of a bleeding diathesis. This is especially true in patients with preexisting haemostatic defects of any kind that may remain compensated, unless platelet function and/or coagulation are not inhibited pharmacologically. To address the dilemma of the “double-edged sword” between thrombosis and bleeding, several strategies are currently under study, including (i) identification of high-risk patients, (ii) stratification of patient subgroups, (iii) individualized decision making, and (iv) administration of “tailor-made” risk-adapted regimens. Nonetheless, prevention and protection from bleeding in patients using antithrombotic agents remain an enduring challenge. For high-risk patients on antiplatelet agents with urgent need of surgery, an algorithm is discussed that allows short-term interruption of oral antithrombotic therapy and i.v. administration of a GPIIb-IIIa receptor antagonist for bridging without increasing peri-operative bleeding. When individual patients, using antiplatelet or anticoagulant agents, experience serious or even life-threatening haemorrhages, haemotherapy with platelet units or prothrombin complex concentrates remains an integral part of the clinical management.

Zusammenfassung

Plättchenfunktionshemmende Substanzen und Antikoagulanzien sind wirksam zur Prävention und Behandlung einer Vielzahl thrombotischer Krankheitsbilder. Verschiedene klinische Situationen erfordern gleichwohl intensivierte anti-thrombotische Therapiekonzepte. Optionen hierfür ergeben sich aus der Kombination von (i) zwei antithrombozytären Substanzen, (ii) antithrombozytärer Monotherapie mit einem Antikoagulans oder (iii) Antikoagulation mit dualer Plättchenfunktionshemmung (Triple-Therapie). Die unter antithrombotischen Behandlungsregimen auftretende Blutungsneigung stellt freilich eine erhebliche Nebenwirkung dar. Dies gilt vor allem für Patienten mit bereits vorhandenen Hämostasestörungen jeglicher Art, die oft kompensiert bleiben können, solange keine pharmakologische Hem-mung von Plättchen und/oder Gerinnung induziert wird. Um dem Dilemma dieses ,,zweischneidigen Schwerts“ mit Thrombose und Blutung zu begegnen, werden derzeit verschiedene Strategien verfolgt: (i) Identifizie-rung von Hochrisiko-Patienten, (ii) Stratifizie-rung von Untergruppen, (iii) individualisierte Entscheidungsprozesse und (iv) ,,maß-geschneiderte“ risikoadaptierte Therapiemaßnahmen. Im Hinblick auf Blutungen bei antithrombotischer Behandlung bleiben Prävention und Protektion gleichwohl eine dauerhafte Herausforderung. Für Hochrisiko-Patienten unter antithrombozytärer Medikation, die sich einer dringlichen Operation zu unterziehen haben, wird ein Algorithmus vorgeschlagen, der eine nur kurzfristige Unterbrechung der oralen antithrombotischen Behandlung und die i.v. Gabe eines GPIIb-IIIaRezeptor-Antagonisten zur Überbrückung vorsieht, ohne das perioperative Blutungsrisiko zu erhöhen. Treten bei einzelnen Patienten während der Einnahme plättchenfunktionsbzw. gerinnungshemmender Medikamenten schwerwiegende, gar lebensbedrohliche Blutungen auf, bleibt die Hämotherapie mit Thrombozyten- bzw. ProthrombinkomplexKonzentraten unverzichtbarer Bestandteil der Behandlung.

Keywords

Antiplatelet drugs - vitamin K antagonists - haemostasis monitoring - clinical trials - platelet transfusions - coagulation factor concentrates

Schlüsselwörter

Antithrombozytäre Substanzen - Vitamin-K Antagonisten - Hämostase-Monitoring - klinische Studien - Thrombozytentransfusionen - Gerinnungsfaktoren-Konzentrate

Full Text

References

References
1 Aguilar M, Hart R. Antiplatelet therapy for preventing stroke in patients with non-valvular atrial fibrillation and no previous history of stroke or transient ischemic attacks. Cochrane Database Syst Rev 2005; 4: CD001925.
2 Ahrens I, Schwarz M, Peter K, Bode C. Therapeutic inhibitors of platelet aggregation – from aspirin to integrin blockers. Transf Med Hemother 2007; 34: 44-54.
3 Alban S. Pharmacology of heparins and direct anticoagulants. Hämostaseologie 2008; 28: 400-420.
4 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.
5 Antithrombotic Trialists’ Collaboration. Baigent C, Blackwell L, Collins R. et al. Asprin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009; 373: 1849-1860.
6 Antman EM, Anbe DT, Armstrong PW. et al. ACC/ AHA Guidelines update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction. J Am Coll Cardiol 2004; 44: E1-E211.
7 Bhatt DL, Topol EJ. Scientific and therapeutic advances in antiplatelet therapy. Nat Rev Drug Discov 2003; 2: 15-28.
8 Braunwald E, Antman E, Beasley J. et al. ACC/AHA Guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction – 2002. Circulation 2002; 106: 1893-1900.
9 Brilakis ES, Banerjee S, Berger PB. Perioperative management of patients with coronary stents. J Am Coll Cardiol 2007; 49: 2145-2150.
10 Budde U, Scharf RE, Franke P. et al. Elevated platelet count as a cause of abnormal von Willebrand factor multimer distribution in plasma. Blood 1994; 82: 475-482.
11 Buller HR, Agnelli G, Hull RD. et al. Antithrombotic therapy for venous thromboembolic disease. Chest 2004; 126: 401S-428S.
12 Cannegieter SC, Rosendaal FR, Wintzen AR. et al. Optimal oral anticoagulaant therapy in patients with mechanical heart valves. N Engl J Med 1995; 333: 11-17.
13 Cattaneo M. New P2Y₁₂ blockers. J Thromb Haemost 2009; 7 (Suppl. 01) 262-265.
14 Chen ZM, Jiang LX, Chen YP. et al. Addition of clopidogrel to aspirin in 45 852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet 2005; 366: 1607-1621.
15 Coller BS. Anti-GPIIb-IIIa drugs: current strategies and future directions. Thromb Haemost 2001; 86: 427-443.
16 Crowther MA, Ginsberg JS, Hirsh J. Practical aspects of anticoagulant therapy. In: Colman RW, Hirsh J, Marder VJ. et al (eds). Hemostasis and Thrombosis. Basic Principles and Clinical Practice. Philadelphia: Lippincott, Williams & Wilkins; 2004: 1497-1516.
17 Eikelboom JW, Mehta SR, Anand SS. et al. Adverse impact of bleeding on prognosis in patients with acute coronary syndromes. Circulation 2006; 114: 774-782.
18 Eikelboom Hirsh J. Combined antiplatelet and anticoagulant therapy: clinical benefits and risks. J Thromb Haemost 2007; 5 (Suppl. 01) 255-263.
19 Fang MC, Chang Y, Hylek EM. et al. Advanced age, anticoagulation intensity, and risk for intracranial hemorrhage among patients taking warfarin for atrial fibrillation. Ann Inter Med 2004; 141: 745-752.
20 Fuster V, Ryden LE, Cannon DS. et al. ACC/AHA/ ESC 2006 Guidelines for the management of patients with atrial fibrillation. Circulation 2006; 114: c257-c354.
21 Gage BF, van Walraven C, Pearce L. et al. Selecting patients with artrial fibrillation for anticoagulation: stroke risk stratification in patients taking aspirin. Circulation 2004; 110: 2287-2292.
22 George JN, Shattil SJ. The clinical importance of acquired abnormalities of platelet function. N Engl J Med 1991; 324: 27-39.
23 Gitter MJ, Jaeger TM, Petterson TM, Silverstein MD. Bleeding and thromboembolism during anticoagulant therapy: a population-based study in Rochester, Minnesota. Mayo Clin Proc 1995; 70: 725-733.
24 Greaves M, Watson HG. Approach to the diagnosis and management of mild bleeding disorders. J Thromb Haemost 2007; 5 (Suppl. 01) 167-174.
25 Hirsch AT, Haskal ZJ, Hertzer NR. et al. ACC/AHA 2005 Practice Guidelines for the management of patients with peripheral arterial disease. Circulation 2006; 113: e463-e654.
26 Hylek EM, Singer DE. Risk factors for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med 1994; 120: 897-902.
27 Joist JH, George JN. Hemostatic abnormalities in liver and renal disease. In: Colman RW, Hirsh J, Marder VJ. et al (eds). Hemostasis and Thrombosis. Basic Principles and Clinical Practice. Philadelphia: Lippincott, Williams & Wilkins,; 2004: 955-973.
28 Langer E, Zimmer S. Established anticoagulants in secondary hemostasis. Hämostaseologie 2009; 29: 241-246.
29 Levi M, Hovingh GK, Cannegieter SC. et al. Bleeding in patients receiving vitamin K antagonists who would hve been excluded from trials on which the indication for anticoagulation was based. Blood 2008; 111: 4471-4476.
30 Levi M. Epidemiology and management of bleeding in patients using vitamin K antagonists. J Thromb Haemost 2009; 7 (Suppl. 01) 103-106.
31 Mangano DT, Miao Vuylsteke A. et al. Mortality associated with aprotinin during five years following coronary artery bypass graft surgery. JAMA 2007; 297: 527-529.
32 Mannuci PM. Desmopressin in the treatment of bleeding disorders: the first 20 years. Blood 1997; 90: 2515-2521.
33 May AE, Geisler T, Gawaz MP. Individualized anti-thrombotic therapy in high risk patients after coronary stenting. A double-edged sword between thrombosis and bleeding. Thromb Haemost 2008; 99: 487-493.
34 Mellemkjaer L, Blot WJ, Sorensen HT. et al. Upper gastrointestinal bleeding among users of NSAIDs: a population-based cohort study in Denmark. Br J Clin Pharmacol 2002; 53: 173-181.
35 Patrono C, Coller BS, FitzGerald GA. et al. Platelet-active drugs: the relationship among dose, effectiveness, and side effects. Chest 2004; 126: 234S-264S.
36 Perzborn E. Factor Xa inhibitors. New anticoagulants for secondary hemostasis. Hämostaseologie 2009; 29: 260-267.
37 Pötzsch B, Scharf RE. Hemostasis-navigated hemo-therapy, diagnosis, management, and monitoring of patients with active bleeding. In: Scharf RE. (ed). Progress and Challenges in Transfusion Medicine, Hemostasis, and Hemotherapy. Freiburg: Karger; 2008: 385-393.
38 Porter A, Konstantino Y, Iakobishvili Z. et al. Short-term triple therapy with aspirin, warfarin, and a thienopyridine among patients undergoing percutaneous coronary intervention. Catheter Cardiovasc Interv 2006; 68: 56-61.
39 Ridell JW, Chiche L, Plaud B, Hamon M. Coronary stents and noncardiac surgery. Circulation 2007; 116: e378-e382.
40 Rothwell PM. External validity of randomised controlled trials: ’to whom do the results of this trial apply?’. Lancet 2005; 365: 82-93.
41 Sabatine MS, Cannon CP, Gibson CM. et al., CLARITY-TIMI 28 Investigators.. Addition of clopidogrel to aspirin and fibrinolysic therapy for myorcardial infarction with ST-segment elevation. N Engl J Med 2005; 352: 1179-1189.
42 Sacco RL, Adams R, Albers G. et al. Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack: a statement for healthcare professionals from the American Heart Association/American Stroke Association Council on Stroke. Circulation 2006; 113: e409-e449.
43 Sadler JE. Aortic stenosis, von Willebrand factor, and bleeding. N Engl J Med 2003; 349: 323-325.
44 Saour JN, Sieck JO, Mamo LA, Gallus AS. Trial of different intensities of anticoagulation in patients with prosthetic heart valves. N Engl J Med 1990; 322: 428-432.
45 Scharf RE. Thrombozyten und Mikrozirkulationsstörungen. Klinische und experimentelle Unter -suchungen zum Sekretionsverhalten und Arachidonsäurestoffwechsel der Blutplättchen. Stuttgart: Schattauer; 1986
46 Scharf RE. In vitro thromboxane synthesis of depleted platelets following renal transplantation. Thromb Haemost 1990; 64: 161-164.
47 Scharf RE. Congenital and acquired platelet function disorders. Hämostaseologie 2003; 23: 170-180.
48 Scharf RE. Acquired platelet function disorders: pathogenesis, classification, frequency, diagnosis, and clinical management. Hämostaseologie 2008; 28: 299-311.
49 Scharf RE. Acquired platelet function defects: an underestimated but frequent cause of bleeding complications in clinical practice. In: Scharf RE. (ed). Progress and Challenges in Transfusion Medicine, Hemostasis, and Hemotherapy. Freiburg: Karger; 2008: 296-316.
50 Scharf RE, Hoffmann T, Kirchhoff EM, Kelm M. Unpublished observations 2009
51 Scharf RE, Hoffmann T. Unpublished observations 2009
52 Schrör K, Hohlfeld T. Acetylsalicylic acid. Weinheim: Wiley VCH; 2009: 94.
53 Schulman S, Beyth RJ, Kearon C, Levine MN. Hemorrhagic complications of anticoagulant and thrombolytic treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2008; 133: 257S-298S.
54 Serebruany VL, Malin AI, Ferguson JJ. et al. Bleeding risks of combination versus single antiplatelet therapy: a meta-analysis of 18 randomized trials comprising 129,314 patients. Fundam Clin Pharmacol 2008; 22: 315-321.
55 Spivak JL. Polycythemia vera and other myeloproliferative diseases. In: Kasper DL, Braunwald E, Fauci AS. et al (eds). Harrison’s Principles of Internal Medicine. New York: McGraw-Hill; 2005: 626-631.
56 Steering Commiittee of the Physicians’ Health Study Research Group.. Final report on the aspirin component of the ongoing Physicians’ Health Study. N Engl J Med 1989; 321: 129-135.
57 Sucker C, Feindt P, Scharf RE. Aortic stenosis, von Willebrand factor, and bleeding. N Engl J Med 2003; 349: 1773-1774.
58 Sugidachi A, Ogawa T, Kurihara A. et al. The greater in vivo antiplatelet effects of prasugrel as compared to clopidogrel reflect more efficient generation of its active metabolite with similar antiplatelet activity to that of clopidogrel’s active metabolite. J Thromb Haemost 2007; 5: 1545-1551.
59 Tcheng JE, Ellis SG, George BS. et al. Pharmacodynamics of chimeric glycoprotein IIb/IIIa integrin antiplatelet antibody Fab 7E3 in high-risk angioplasty. Circulation 1994; 90: 1757-1764.
60 Vincentelli A, Susen S, Le Torneau T. et al. Acquires von Willebrand syndrome in aortic stenosis. N Engl J Med 2003; 349: 343-349.
61 Working Group for the Study of Patient Self-Management of Oral Anticoagulation.. A structured teaching and self-management program for patients receiving oral anticoagulation. JAMA 1999; 281: 145-150.
62 Yusuf S, Zhao F, Mehta SR. et al. 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.
63 Zotz RB, Scharf RE. Recombinant factor VIIa in patients with platelet function disorders or thrombocytopenia. Hämostaseologie 2007; 27: 251-262.