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Hamostaseologie 2001; 21(01): 22-29
DOI: 10.1055/s-0037-1619501
Original article
Schattauer GmbH

Hämostasestörungen durch Analgetika, Antiphlogistika und Antirheumatika

Hemostatic side effects of analgesic, antiphlogistic and antirheumatic drugs
Th. Hohlfeld
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Publication Date:
27 December 2017 (online)

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Zusammenfassung

Nichtsteroidale Antiphlogistika/Analgetika wie Azetylsalizylsäure (ASS), Indometazin, Diclofenac, Naproxen und Piroxicam hemmen die thrombozytäre Thromboxansynthese und damit die Thrombozytenfunktion. Auch in therapeutischer Dosierung können diese Verbindungen daher zu Blutungskomplikationen führen. Wohl am besten untersucht ist hier das Risiko gastrointestinaler Blutungen, welches bei Behandlung mit Metamizol, Propyphenazon und Paracetamol vergleichsweise gering, unter Indometazin, Diclofenac, Naproxen und Azetylsalizylsäure (ASS) höher und bei Piroxicam relativ gesehen am höchsten ist. Eine direkte Schädigung der Magen- und Duodenalschleimhaut trägt bei diesen Substanzen zum gastrointestinalen Blutungsrisiko bei. Selektive Inhibitoren der induzierbaren Zyklooxygenase (COX-2), wie Celecoxib und Rofecoxib, haben nach bisheriger Erfahrung nur selten zu gastrointestinalen Blutungen geführt. Glukokortikoide beeinflussen in mehrfacher Weise die Hämostase. Zunächst ist hier eine Stimulation der hepatischen Synthese verschiedener Gerinnungsfaktoren (I, II, V, VII, VIII, IX, XI, XII) bekannt. Darüber hinaus können Glukokortikoide auch eine Hypofibrinolyse bewirken, wahrscheinlich infolge erhöhter Aktivität von Inhibitoren der Fibrinolyse (PAI-1, α2-Antiplasmin). Im Rahmen einer Behandlung mit antirheumatischen Basistherapeutika (darunter Goldsalze, Penicillamin, Methotrexat) ist vor allem auf nicht ganz seltene Thrombozytopenien immunologischer oder myelotoxischer Genese zu achten. Von praktischer Bedeutung sind auch Arzneimittelinteraktionen, wie z.B. eine Steigerung des Blutungsrisikos durch Antikoagulanzien (Warfarin-Derivate, Heparine) bei gleichzeitiger Behandlung mit nichtsteroidalen Antiphlogistika und Analgetika, wozu neben der synergistischen Wirkung auf Thrombozyten und das plasmatische Gerinnungssytem auch pharmakokinetische Mechanismen beitragen können.

Summary

Non-steroidal antiinflammatory drugs like acetylsalicyclic acid, indomethacin, diclofenac, naproxen and piroxicam suppress platelet thromboxane formation and are inhibitors of platelet function. Bleeding complications may occur at therapeutic (analgesic and antiinflammatory) dosages. The relative risk of gastrointestinal bleeding is different according to the individual compound. It is relatively low for paracetamol, metamizol and propyphenazon and higher for indomethacin, diclofenac and mefenamic acid. Piroxicam appears to be associated with a rather high risk, possibly due to its long half life and the potential to accumulate. In addition to platelet inhibition, a toxic action on gastric and duodenal mucosa contributes to the increased risk of gastrointestinal bleeding. Selective inhibitors of the inducible isoform of cyclooxygenase (COX-2), including celecoxib and rofecoxib, appear to be rather safe with respect to gastrointestinal and other bleeding complications. Glucocorticoids have several effects on hemostasis. First, the hepatic synthesis of a number of coagulation factors (I, II, V, VII, VIII, IX, XI, XII) is increased. Second, corticosteroids inhibit endogenous fibrinolysis, probably by an increased activity of antifibrinolytic proteins, such as PAI-1 and α2-antiplasmin. The main hemostatic risk of the disease modifying antirheumatic drugs (DMARDs), such as gold compounds, penicillamine and methotrexate, is thrombocytopenia. Both, immunological and myelotoxic mechanisms may be involved. Relevant drug interactions exerted by co-administration of non-steroidal antiinflammatory compounds with anticoagulant drugs (warfarin derivatives, heparins) include an increased risk for bleeding, resulting from a synergistic inhibition of both clot formation and platelet activation. In addition, pharmacokinetic interactions may also be involved.

Schlüsselwörter

Zyklooxigenase - Glukokortikoide - Gerinnungsfaktoren - antirheumatische Basistherapeutika

Keywords

Cyclooxygenase - glucocorticoids - coagulation factors - antirheumatic drugs
 

  • Literatur

  • 1 Douthwaite AH. Some recent advances in medical diagnosis and treatment. Br Med J 1938; 1: 1143-6.
    CrossrefPubMedGoogle Scholar
  • 2 Hurst A, Lintott GAM. Aspirin as a cause of hematemesis. Guys Hosp Rep 1939; 11: 627-34.
    PubMedGoogle Scholar
  • 3 Kaufman DW, Kelly JP, Sheehan JE, Laszlo A, Wiholm BE, Alfredsson L, Koff RS, Shapiro S. Nonsteroidal anti-inflammatory drug use in relation to major upper gastrointestinal bleeding. Clin Pharmacol Ther 1993; 53: 485-94.
    CrossrefPubMedGoogle Scholar
  • 4 Vane JR, Bakhle YS, Botting RM. Cyclooxygenases 1 and 2. Annu Rev Pharmacol Toxicol 1998; 38: 97-120.
    CrossrefPubMedGoogle Scholar
  • 5 Gershlick AH. Antiplatelet therapy. Hosp Med 2000; 61: 15-23.
    CrossrefPubMedGoogle Scholar
  • 6 Antiplatelet Trialists’ Collaboration. Collaborative overview of randomised trials of antiplatelet therapy-I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Br Med J 1994; 308: 81-106.
    CrossrefPubMedGoogle Scholar
  • 7 Schrör K. Acetylsalizylsäure. Thieme; Stuttgart: 1992
    Google Scholar
  • 8 Schrör K. Grundlagen der antithrombotischen Wirkung von Azetylsalizylsäure. In: Schrör K, Breddin HK. eds. Azetylsalizylsäure im kardiovaskulären System. Birkhäuser; Basel: 1996: 36-57.
    Google Scholar
  • 9 Hohlfeld T. Pharmakokinetik von Acetylsalizylsäure. In: Schrör K, Breddin HK. eds. Acetylsalizylsäure im kardiovaskulären System. Birkhäuser; Basel: 1996: 12-31.
    Google Scholar
  • 10 Seymour RA, Williams FM, Oxley A, Ward A, Fearns M, Brighan K, Rawlins MD, Jones PM. A comparative study of the effects of aspirin and paracetamol (acetaminophen) on platelet aggregation and bleeding time. Eur J Clin Pharmacol 1984; 26: 567-71.
    CrossrefPubMedGoogle Scholar
  • 11 Schoen RT, Vender RJ. Mechanisms of nonsteroidal anti-inflammatory drug-induced gastric damage. Am J Med 1989; 86: 449-58.
    CrossrefPubMedGoogle Scholar
  • 12 Lee M, Cryer B, Feldman M. Dose effects of aspirin on gastric prostaglandins and stomach mucosal injury. Ann Intern Med 1994; 120: 184-9.
    CrossrefPubMedGoogle Scholar
  • 13 Fiore LD, Brophy MT, Lopez A, Janson P, Deykin D. The bleeding time response to aspirin. Identifying the hyperresponder. Am J Clin Pathol 1990; 94: 292-6.
    CrossrefPubMedGoogle Scholar
  • 14 The Dutch TIA Trial Study Group. A comparison of two doses of aspirin (30 mg vs. 283 mg a day) in patients after a transient ischemic attack or minor ischemic stroke. N Engl J Med 1991; 325: 1261-6.
    CrossrefPubMedGoogle Scholar
  • 15 The SALT Collaborative Group. Swedish Aspirin Low-Dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events. Lancet 1991; 338: 1345-9.
    CrossrefPubMedGoogle Scholar
  • 16 Landefeld CS, Beyth RJ. Anticoagulant-related bleeding: clinical epidemiology, prediction, and prevention. Am J Med 1993; 95: 315-28.
    CrossrefPubMedGoogle Scholar
  • 17 Radke J. Analgetika. In: Müller-Örlinghausen B, Lasek R, Düppenbecker H, Munter KH. eds. Handbuch der unerwünschten Arzneimittelwirkungen. Urban & Fischer; München: 1999: 3-21.
    Google Scholar
  • 18 Davies RO. Review of the animal and clinical pharmacology of diflunisal. Pharmacotherapy 1983; 3: 9S-22S.
    CrossrefPubMedGoogle Scholar
  • 19 Danesh BJ, Saniabadi AR, Russell RI, Lowe GD. Therapeutic potential of choline magnesium trisalicylate as an alternative to aspirin for patients with bleeding tendencies. Scott Med J 1987; 32: 167-8.
    CrossrefPubMedGoogle Scholar
  • 20 Stuart JJ, Pisko EJ. Choline magnesium trisalicylate does not impair platelet aggregation. Pharmatherapeutica 1981; 2: 547-51.
    PubMedGoogle Scholar
  • 21 Pedersen-Bjergaard U, Andersen M, Hansen PB. Drug-induced thrombocytopenia: clinical data on 309 cases and the effect of corticosteroid therapy. Eur J Clin Pharmacol 1997; 52: 183-9.
    CrossrefPubMedGoogle Scholar
  • 22 McIntyre BA, Philp RB, Inwood MJ. Effect of ibuprofen on platelet function in normal subjects and hemophiliac patients. Clin Pharmacol Ther 1978; 24: 616-21.
    CrossrefPubMedGoogle Scholar
  • 23 Dominguez-Jimenez C, Diaz-Gonzalez F, Gonzalez-Alvaro I, Cesar JM, Sanchez-Madrid F. Prevention of alpha IIb beta3 activation by non-steroidal antiinflammatory drugs. FEBS Lett 1999; 446: 318-22.
    CrossrefPubMedGoogle Scholar
  • 24 O’Brien JR, Finch W, Clark E. A comparison of an effect of different anti-inflammatory drugs on human platelets. J Clin Pathol 1970; 23: 522-5.
    CrossrefPubMedGoogle Scholar
  • 25 De-Gaetano G, Donati MB, Vermylen J. Some effects of indomethacin on platelet function, blood coagulation and fibrinolysis. Int Z Klin Pharmakol Ther Toxikol 1971; 5: 196-9.
    PubMedGoogle Scholar
  • 26 Rane A, Oelz O, Frolich JC, Seyberth HW, Sweetman BJ, Watson JT, Wilkinson GR, Oates JA. Relation between plasma concentration of indomethacin and its effect on prostaglandin synthesis and platelet aggregation in man. Clin Pharmacol Ther 1978; 23: 658-68.
    CrossrefPubMedGoogle Scholar
  • 27 Niemi TT, Taxell C, Rosenberg PH. Comparison of the effect of intravenous ketoprofen, ketorolac and diclofenac on platelet function in volunteers. Acta Anaesthesiol Scand 1997; 41: 1353-8.
    CrossrefPubMedGoogle Scholar
  • 28 Zimmerman J, Siguencia J, Tsvang E. Upper gastrointestinal hemorrhage associated with cutaneous application of diclofenac gel. Am J Gastroenterol 1995; 90: 2032-4.
    PubMedGoogle Scholar
  • 29 Thiagarajan J, Bates S, Hitchcock M, Morgan HJ. Blood loss following tonsillectomy in children. A blind comparison of diclofenac and papaveretum. Anaesthesia 1993; 48: 132-5.
    PubMedGoogle Scholar
  • 30 Price AJ, Obeid D. Spontaneous non-gastrointestinal bleeding associated with diclofenac. Lancet 1989; 2: 1520.
    PubMedGoogle Scholar
  • 31 Khazan U, Toth M, Mutgi A. Diclofenac sodium and bruising. Ann Intern Med 1990; 112: 472-3.
    PubMedGoogle Scholar
  • 32 Knijff-Dutmer EA, Martens Avd, Laar MA. Effects of nabumetone compared with naproxen on platelet aggregation in patients with rheumatoid arthritis. Ann Rheum Dis 1999; 58: 257-9.
    CrossrefPubMedGoogle Scholar
  • 33 Cronberg S, Wallmark E, Soderberg I. Effect on platelet aggregation of oral administration of 10 non-steroidal analgesics to humans. Scand J Haematol 1984; 33: 155-9.
    CrossrefPubMedGoogle Scholar
  • 34 de Meijer A, Vollaard H, de Metz M, Verbruggen B, Thomas C, Novakova I. Meloxicam, 15 mg/day, spares platelet function in healthy volunteers. Clin Pharmacol Ther 1999; 66: 425-30.
    CrossrefPubMedGoogle Scholar
  • 35 Willoughby DA, Moore AR, Colville NP. COX-1, COX-2, and COX-3 and the future treatment of chronic inflammatory disease. Lancet 2000; 355: 646-8.
    CrossrefPubMedGoogle Scholar
  • 36 Fischereder M, Jaffe JP. Thrombocytopenia following acute acetaminophen overdose. Am J Hematol 1994; 45: 258-9.
    CrossrefPubMedGoogle Scholar
  • 37 Simon LS, Weaver AL, Graham DY, Kivitz AJ, Lipsky PE, Hubbard RC, Isakson PC, Verburg KM, Yu SS, Zhao WW. et al. Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis: a randomized controlled trial. JAMA 1999; 282: 1921-8.
    CrossrefPubMedGoogle Scholar
  • 38 Emery P, Zeidler H, Kvien TK, Guslandi M, Naudin R, Stead H, Verburg KM, Isakson PC, Hubbard RC, Geis GS. Celecoxib versus diclofenac in long-term management of rheumatoid arthritis: randomised double-blind comparison. Lancet 1999; 354: 2106-11.
    CrossrefPubMedGoogle Scholar
  • 39 Bombardier C. VIOXX gastrointestinal outcome Research (VIGOR). Präsentation beim Annual European Congress of Rheumatology. Juni 2000, Nizza.
    PubMedGoogle Scholar
  • 40 Silverstein FE, Faich G, Goldstein JL, Simon LS, Pincus T, Whelton A, Makuch R, Eisen G, Agrawal NM, Stenson WF. et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study. JAMA 2000; 284: 1247-55.
    CrossrefPubMedGoogle Scholar
  • 41 Ozsoylu S, Strauss HS, Diamond LK. Effects of corticosteroids on coagulation of the blood. Nature 1962; 195: 1214-5.
    CrossrefPubMedGoogle Scholar
  • 42 Dal-Bo-Zanon R, Fornasiero L, Boscaro M, Cappellato G, Fabris F, Girolami A. Increased factor VIII associated activities in Cushing’s syndrome: a probable hypercoagulable state. Thromb Haemost 1982; 47: 116-7.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 43 Patrassi GM, Dal-Bo-Zanon R, Boscaro M, Martinelli S, Girolami A. Further studies on the hypercoagulable state of patients with Cushing’s syndrome. Thromb Haemost 1985; 54: 518-20.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 44 Li M, Ye X, Woodward RN, Zhu C, Nichols LA, Holland LJ. Analysis of the DNA-binding site for Xenopus glucocorticoid receptor accessory factor. Critical nucleotides for binding specificity in vitro and for amplification of steroid-induced fibrinogen gene transcription. J Biol Chem 1998; 273: 9790-6.
    CrossrefPubMedGoogle Scholar
  • 45 Stötzer H. Toxische Arzneimittelwirkungen. Fischer; Stuttgart: 1995: 96
    Google Scholar
  • 46 Small M, Lowe GD, Forbes CD, Thomson JA. Thromboembolic complications in Cushing’s syndrome. Clin Endocrinol Oxf 1983; 19: 503-11.
    CrossrefPubMedGoogle Scholar
  • 47 Derex L, Giraud P, Hanss M, Riche H, Nighoghossian N, Trouillas P. Spontaneous intracerebral hemorrhage revealing Addison’s disease. Cerebrovasc Dis 1998; 8: 240-3.
    CrossrefPubMedGoogle Scholar
  • 48 Chaudhuri MD, Bhan GL. Deep vein thrombosis: a side effect of steroid therapy. Br J Clin Pract 1984; 38: 118-9.
    PubMedGoogle Scholar
  • 49 Sartori TM, Maurizio PG, Sara P, Ugolino L, Annalisa A, Panagiotis T, Massimo F, Antonio G. Relation between long-term steroid treatment after heart transplantation, hypofibrinolysis and myocardial microthrombi generation. J Heart Lung Transplant 1999; 18: 693-700.
    CrossrefPubMedGoogle Scholar
  • 50 Patrassi GM, Sartori MT, Rigotti P, Di-Landro D, Theodoridis P, Fioretti M, Capalbo M, Saggiorato G, Boeri G, Girolami A. Reduced fibrinolytic potential one year after kidney transplantation. Relationship to long-term steroid treatment. Transplantation 1995; 59: 1416-20.
    CrossrefPubMedGoogle Scholar
  • 51 Ueda N. Effect of corticosteroids on some hemostatic parameters in children with minimal change nephrotic syndrome. Nephron 1990; 56: 374-8.
    CrossrefPubMedGoogle Scholar
  • 52 Stafford BT, Crosby WH. Late onset of gold-induced thrombocytopenia. With a practical note on the injections of dimercaprol. JAMA 1978; 239: 50-1.
    CrossrefPubMedGoogle Scholar
  • 53 Swanson M, Cook R. Detection of drug-induced blood dyscrasias. Am J Hosp Pharm 1973; 30: 534-7.
    PubMedGoogle Scholar
  • 54 Taylor HG, Samanta A. Penicillamine in rheumatoid arthritis. A problem of toxicity. Drug Saf 1992; 7: 46-53.
    CrossrefPubMedGoogle Scholar
  • 55 Diana FJ, Veronich K, Kapoor AL. Binding of nonsteroidal anti-inflammatory agents and their effect on binding of racemic warfarin and its enantiomers to human serum albumin. J Pharm.Sci 1989; 78: 195-9.
    PubMedGoogle Scholar
  • 56 Chan TY. Adverse interactions between warfarin and nonsteroidal antiinflammatory drugs: mechanisms, clinical significance, and avoidance. Ann Pharmacother 1995; 29: 1274-83.
    CrossrefPubMedGoogle Scholar
  • 57 Banfield C, O’Reilly R, Chan E, Rowland M. Phenylbutazone-warfarin interaction in man: further stereochemical and metabolic considerations. Br J Clin Pharmacol 1983; 16: 669-75.
    CrossrefPubMedGoogle Scholar
  • 58 Masche UP, Rentsch KM, von Felten A, Meier PJ, Fattinger KE. Opposite effects of lornoxicam co-administration on phenprocoumon pharmacokinetics and pharmacodynamics. Eur J Clin Pharmacol 1999; 54: 857-64.
    CrossrefPubMedGoogle Scholar
  • 59 Oler A, Whooley MA, Oler J, Grady D. Adding heparin to aspirin reduces the incidence of myocardial infarction and death in patients with unstable angina. A meta-analysis. JAMA 1996; 276: 811-5.
    CrossrefPubMedGoogle Scholar
  • 60 Futterman LG, Lemberg L. Low-molecular-weight heparin: an antithrombotic agent whose time has come. Am J Crit Care 1999; 8: 520-3.
    PubMedGoogle Scholar
  • 61 Herbert JM, Dol F, Bernat A, Falotico R, Lale A, Savi P. The antiaggregating and antithrombotic activity of clopidogrel is potentiated by aspirin in several experimental models in the rabbit. Thromb Haemost 1998; 80: 512-8.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 62 Wittke B, Ensor H, Chung J, Birnbock H, Lausecker B, Ertel SI, Mackie IJ, Machin SJ. Pharmacokinetics and pharmacodynamics of sibrafiban alone or in combination with ticlopidine and aspirin. Br. J Clin.Pharmacol 2000; 49: 231-9.
    PubMedGoogle Scholar
  • 63 Bertrand ME, Rupprecht HJ, Urban P, Gershlick AH. Investigators f. 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: 624-9.
    CrossrefPubMedGoogle Scholar
  • 64 Lablanche JM, McFadden EP, Bonnet JL, Grollier G, Danchin N, Bedossa M, Leclercq C, Vahanian A, Bauters C, Van-Belle E. et al. Combined antiplatelet therapy with ticlopidine and aspirin. A simplified approach to intracoronary stent management. Eur Heart J 1996; 17: 1373-80.
    CrossrefPubMedGoogle Scholar
  • 65 Laporte JR, Carne X, Vidal X, Moreno V, Juan J. Upper gastrointestinal bleeding in relation to previous use of analgesics and non-steroidal anti-inflammatory drugs. Catalan Countries Study on Upper Gastrointestinal Bleeding. Lancet 1991; 337: 85-9.
    CrossrefPubMedGoogle Scholar