Download PDF
Hamostaseologie 2011; 31(01): 28-40
DOI: 10.5482/ha-1145
Review
Schattauer GmbH

The impact and management of acquired platelet dysfunction

Bedeutung und Behandlung erworbener Plättchen funktionsstörungen
R. E. Scharf
1   Department of Experimental and Clinical Haemostasis, Haemotherapy and Transfusion Medicine, and Haemophilia Comprehensive Care Center, Heinrich Heine University Medical Center, Düsseldorf, Germany
,
M. M. Rahman
1   Department of Experimental and Clinical Haemostasis, Haemotherapy and Transfusion Medicine, and Haemophilia Comprehensive Care Center, Heinrich Heine University Medical Center, Düsseldorf, Germany
2   Division of Haematology, Dhaka Medical College Hospital, Dhaka, Bangladesh
,
H. Seidel
1   Department of Experimental and Clinical Haemostasis, Haemotherapy and Transfusion Medicine, and Haemophilia Comprehensive Care Center, Heinrich Heine University Medical Center, Düsseldorf, Germany
› Author Affiliations Acknowledgements: This work was supported in part by grants of the Deutsche Forschungsgemeinschaft (Scha 358/3–1 and Sonderforschungsbereich 612 „Molecular analysis of cardiovascular functions and dysfunctions“, TPB2 „Modulation of platelet thrombogenicity through genetically determined variants of platelet integrins“). Additional support was provided by the Biological Medical Research Center, Heinrich Heine University, Düsseldorf. We thank Prof. Zaverio M. Ruggeri, The Scripps Research Institute, La Jolla, CA, USA, for providing monoclonal antibodies (LJ-P4, LJ-CP8, and LJ-Ibα) and purified human fibrinogen; Prof. Sanford J. Shattil and Prof. Mark H. Ginsberg, Department of Medicine, University of California San Diego, La Jolla, CA, USA, for PAC1 and anti-LIBS1, respectively. Dr. M. Mizanur Rahman is recipient of a fellowship (“Reach the World Education Program”) from the International Society on Thrombosis and Haemostasis.
Further Information

Publication History

Publication Date:
27 December 2017 (online)

Also available at
    Permissions and Reprints

Summary

Platelet function can be abnormally increased, as in association with acute vascular events, or defective, as in a variety of clinical settings. Acquired platelet dysfunction may occur at any age and range in severity from mild to life-threatening haemorrhages. Diagnostic work-up of platelet disorders requires meticulous evaluation of medical history, specifically of any drugs interfering with platelet function, careful clinical examination and a staged laboratory protocol to assess the underlying platelet defect(s). To identify hyperactive platelets ex vivo, costly procedures may be required using flow cytometry and distict epitope-specific monoclonal antibodies. Currently, this approach can be recommended for research purposes only. Drugs represent the most common cause of platelet dysfunction in our overmedicated society. While aspirin, clopigogrel (more recently also prasugrel) and integrin αIIbβ3 (GPIIb-IIIa) receptor antagonists (ab-ciximab, eptifibatide and tirofiban) are well-known prototypes of antiplatelet drugs, other widely used agents (e.g. nonsteroidal anti-inflammatory drugs, antibiotics, serotonin reup-take inhibitors and volume expanders) can also impair platelet function and thus cause or aggravate hemorrhages. Identification of individual patients with pre-existing hemostatic defects remains crucial (i) to prevent bleeding complications, (ii) to manage symptoms adequately, (iii) to minimize the risk from invasive procedures, and (iv) to avoid unnecassary exposure to blood products. Screening for platelet dysfunction can be performed by point-of-care testing followed by platelet aggregometry in response to various agonists. While mild bleeding episodes due to antiplatelet therapy can be managed by withdrawal of the drug(s), severe hemorrhages may require immediate platelet transfusions. Apart from that, the prohemostatic armamentarium is limited to desmopressin, antifi-brinolytic agents, and recombinant factor VIIa.

Zusammenfassung

Thrombozytäre Funktionen können abnorm gesteigert sein, etwa bei akuten vaskulären Ereignissen, oder – im Gefolge einer Vielzahl von Krankheitsbildern – Defekte aufweisen (Thrombozytopathien). Defizitäre Plättchenstörungen treten in jedem Lebensalter auf und können leichte bis lebensbedrohliche Blutungen hervorrufen. Die exakte Zuordnung thrombozytärer Störungen erfordert eine genaue Erhebung der Vorgeschichte einschließlich einer akribischen Medikamentenanamnese, besonders von Substanzen, die mit Plättchenfunktionen interferieren können, ebenso eine sorgfältige klinische Untersuchung und laboranalytische Stufen-diagnostik. Zum Nachweis hyperaktiver Plättchen ex vivo können aufwändige, kosteninten-sive Verfahren wie durchflusszytometrische Un-tersuchungen unter Einsatz epitopspezifischer monoklonaler Antikörper erforderlich werden. Allerdings sollten solche Techniken zurzeit auf Forschungsvorhaben beschränkt bleiben. Bei dem hohen Medikamentenkonsum überrascht es nicht, dass Pharmaka die Hauptursache er-worbener Plättchenfunktionsstörungen dar-stellen. Typische antithrombozytäre Substanzen sind Azetylsalizylsäure, Clopidogrel (neuerdings Prasugrel) und Integrin αIIbβ3 (GPIIb-IIIa)-Re-zeptorantagonisten (Abciximab, Eptifibatid und Tirofiban). Daneben können andere häufig ein-gesetzte Medikamente wie nichtsteroidale entzündungshemmende Substanzen, Antibiotika, Serotonin-Wiederaufnahme-Inhibitoren und Volumenexpander die Plättchenfunktion beein-trächtigen und eine Blutungsneigung bedingen oder verstärken. Die Identifizierung einezelner Patienten mit vorbestehenden Hämostasede-fekten ist entscheidend, um (i) Blutungskomplikationen vorzubeugen, (ii) Symptome adäquat zu behandeln, (iii) Risken invasiver Verfahren zu minimieren und (iv) eine unnötige Exposition gegenüber Blutprodukten zu vermeiden. Als Screening-Verfahren einer gestörten Plättchen-funktion werden zunächst Point-of-Care-Techniken, anschließend die Thrombozytenaggrego-metrie nach Plättchenstimulation mit verschie-denen Agonisten eingesetzt. Bei geringer Blutung infolge antithrombozytärer Therapie ge-nügt in der Regel das Absetzen des Medikaments. Schwerwiegende Blutungen können hingegen die sofortige Transfusion von Throm-bozytenkonzentraten erfordern. Das übrige Behandlungsspektrum zur Blutstillung beschränkt sich auf den Einsatz von Desmopressin, Antifi-brinolytika und rekombinanten Faktor VIIa.

Keywords

Platelet hyperaggregability - prothrombotic states - antiplatelet agents - acquired platelet dysfunction - bleeding - haemotherapy

Schlüsselwörter

Plättchenhyperaggregabilität - prothrombotische Zustände - antithrombozytäre Substanzen - erworbene Plättchenfunktionsdefekte - Blutungen - Hämotherapie
 

  • References

  • 1 Fuster V, Badimon L, Badimon JJ, Chesbro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med 1992; 326: 242-250.
    CrossrefPubMedGoogle Scholar
  • 2 Ruggeri ZM. Platelet interactions with vessel wall components during thrombogenesis. Blood Cell Mol Dis 2006; 47: 1903-1910.
    PubMedGoogle Scholar
  • 3 Ruggeri ZM, Mendolicchio GL. Adhesion mechanisms in platelet function. Circ Res 2007; 100: 1673-1685.
    CrossrefPubMedGoogle Scholar
  • 4 Iannacone M, Sitia G, Isogawa M. et al. Platelets prevent IFN-alpha/beta-induced lethal hemorrhage promoting CTL-dependent clearance of lymphocytic choriomeningitis virus. Proc Natl Acad Sci USA 2008; 105: 629-634.
    CrossrefPubMedGoogle Scholar
  • 5 Wagner DD, Burger PC. Platelets in inflammation and thrombosis. Arterioscl Thromb Vasc Biol 2003; 23: 2131-2137.
    CrossrefPubMedGoogle Scholar
  • 6 Boucharaba A, Serre CM, Grès S. et al. Platelet-derived lysophosphatidic acid supports the progression of osteolytic bone metastases in breast cancer. J Clin Invest 2004; 114: 1714-1725.
    CrossrefPubMedGoogle Scholar
  • 7 Gupta GP, Massagué J. Platelets and metastasis: a novel fatty link. J Clin Invest 2004; 114: 1691-1693.
    CrossrefPubMedGoogle Scholar
  • 8 Ruggeri ZM. Platelet adhesion under flow. Microcirculation 2009; 116: 58-83.
    PubMedGoogle Scholar
  • 9 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; 04: CD001925.
    PubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 11 Antithrombotic Trialists’ (ATT) 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 randomized trials. Lancet 2009; 373: 1849-1860.
    CrossrefPubMedGoogle Scholar
  • 12 Scharf RE. Management of bleeding in patients using antithrombotic agents: Prediction, prevention, protection and problem-oriented intervention. Hämostaseologie 2009; 29: 388-398.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 13 Eikelboom Hirsh J. Combined antiplatelet and anticoagulant therapy: clinical benefits and risks. J Thromb Haemost 2007; 05 (Suppl. 01) 255-263.
    CrossrefPubMedGoogle Scholar
  • 14 May AE, Geisler T, Gawaz MP. Individualized antithrombotic therapy in high risk patients after coronary stenting. A double-edged sword between thrombosis and bleeding. Thromb Haemost 2008; 99: 487-493.
    PubMedGoogle Scholar
  • 15 Scharf RE. Acquired platelet function defects: an underestimated but frequent cause of bleeding complications in clinical practice. In: Scharf RE. Progress and Challenges in Transfusion Medicine, Hemostasis, and Hemotherapy. Freiburg: Karger; 2008: 296-316.
    Google Scholar
  • 16 Fitzgerald DJ, Roy L, Catella F, FitzGerald GA. Platelet activation in unstable coronary disease. N Engl J Med 1986; 315: 983-989.
    CrossrefPubMedGoogle Scholar
  • 17 Scharf RE. Thrombozyten und Mikrozirkulationsstörungen. Stuttgart, New York, Schattauer: 1986
    Google Scholar
  • 18 Scharf RE, Tomer A, Marzec UM. et al. Activation of platelets in blood perfusing angioplasty-damaged coronary arteries. Flow cytometric detection. Arterioscler Thromb Vasc Biol 1992; 12: 1475-1487.
    PubMedGoogle Scholar
  • 19 Hannington E, Jones RJ, Amess JAL, Wachowicz B. Migraine: a platelet disorder. Lancet 1981; 02: 720.
    PubMedGoogle Scholar
  • 20 Davies JA, McNicol GP. Detection of a prethrombotic state. In: Bloom AL, Thomas DP. Edinburgh, London: Churchill Livingstone; 1981: 593-609.
    Google Scholar
  • 21 Yee DL, Sun CW, Bergeron AL. et al. Aggregometry detects platelet hyperreactivity in healthy individuals. Blood 2005; 106: 2723-2729.
    CrossrefPubMedGoogle Scholar
  • 22 Trip MD, Cats VM, van Capelle FJL, Vreeken J. Platelet hyperreactivity and prognosis in survivors of myocardial infarction. N Engl J Med 1990; 322: 1549-1554.
    CrossrefPubMedGoogle Scholar
  • 23 Mammen EF. Sticky platelet syndrom. Semin Thromb Hemost 1999; 25: 361-365.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 24 Kunicki TJ, Newman PJ. The molecular immunology of human platelet proteins. Blood 1992; 80: 1386-1404.
    PubMedGoogle Scholar
  • 25 Newman PJ, Derbes RS, Aster RH. The human platelet alloantigens, PlA1 and PlA2, are associated with a leucine 33/proline 33 amino acid polymorphism in membrane GPIIIa, and are distinguishable by DNA typing. J Clin Invest 1989; 83: 1778-1781.
    CrossrefPubMedGoogle Scholar
  • 26 Kunicki TJ, Kritzik M, Annis DS, Nugent DJ. Hereditary variation in platelet alpha2 beta1 density is associated with two silent polymorphisms in the alpha 2 coding sequence. Blood 1997; 89: 1939-1943.
    PubMedGoogle Scholar
  • 27 Kritzik M, Savage B, Nugent DJ. et al. Nucleotide polymorphisms in the alpha 2 gene define multiple alleles that are associated with differences in platelet alpha2 beta1 density. Blood 1998; 92: 2382-2388.
    PubMedGoogle Scholar
  • 28 Weiss EJ, Bray PF, Tayback M. et al. A polymorphism of a platelet glycoprotein receptor as an inherited risk factor for coronary thrombosis. N Engl J Med 1996; 334: 1090-1094.
    CrossrefPubMedGoogle Scholar
  • 29 Ridker PM, Hennekens CH, Schmitz C. et al. Pl A1/A2 polymorphism of platelet glycoprotein IIIa and the risks of myocardial infarction, stroke,, and venous thrombosis. Lancet 1997; 349: 385-388.
    CrossrefPubMedGoogle Scholar
  • 30 Zotz RB, Scharf RE. Platelet receptor polymorphisms and their role in cardiovascular disease. J Lab Med 2002; 26: 584-593.
    PubMedGoogle Scholar
  • 31 Scharf RE, Zotz RB. Blood platelets and myocardial infarction: do hyperactive platelets really exist? Transfus Med Hemother. 2006; 33: 189-199.
    PubMedGoogle Scholar
  • 32 Moshfegh F, Wuillemin WA, Redondo M. et al. Association of two silent polymorphisms of platelet glycoprotein Ia-IIa receptor with risk of myocardial infarction: a case-control study. Lancet 1999; 353: 351-354.
    CrossrefPubMedGoogle Scholar
  • 33 Santoso S, Kunicki TJ, Kroll H. et al. Associations of the platelet glycoprotein Ia C807T gene polymorphism with nonfatal myocardial infarction in younger patients. Blood 1999; 93: 2449-2453.
    PubMedGoogle Scholar
  • 34 Zotz RB, Winkelmann BR, Nauck M. et al. Polymorphism of platelet membrane glycoprotein IIIa: Human platelet antigen 1b (HPA-1b/PlA2) is an inherited risk factor for premature myocardial infarction in coronary artery disease. Thromb Haemost 1998; 79: 731-735.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 35 Zotz RB, Klein M, Dauben HP. et al. Prospective analysis of patients after coronary-artery bypass grafting: Platelet GPIIIa polymorphism (HPA1/PlA2) is an inherited risk factor for bypass occlusion, myocardial infarction, and death. Thromb Haemost 2000; 81: 404-407.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 36 Bray PF. Platelet glycoprotein polymorphisms as risk factors for thrombosis. Curr Opin Hematol 2000; 07: 284-289.
    CrossrefPubMedGoogle Scholar
  • 37 Zotz RB, Winkelmann BR, Müller C. et al. Association of polymorphisms of platelet membrane integrins αIIbβ3 (HPA-1b/ PlA2) and α2β1 (α2807TT) with premature myocardial infarction. J Thromb Haemost 2005; 03: 1522-1529.
    CrossrefPubMedGoogle Scholar
  • 38 Savage B, Saldivar E, Ruggeri ZM. Initiation of platelet adhesion by arrest onto fibrinogen or translocation on von Willebrand factor. Cell 1996; 84: 289-297.
    CrossrefPubMedGoogle Scholar
  • 39 Savage B, Almus-Jacobs F, Ruggeri ZM. Specific syergy of multiple substrate-receptor interactions in platelet thrombus formation under flow. Cell 1998; 94: 657-666.
    CrossrefPubMedGoogle Scholar
  • 40 Ruggeri ZM. Von Willebrand factor, platelets and endothelial cell interactions. J Thromb Haemost 2003; 01: 1335-1342.
    CrossrefPubMedGoogle Scholar
  • 41 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.
    CrossrefPubMedGoogle Scholar
  • 42 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.
    CrossrefPubMedGoogle Scholar
  • 43 Brilakis ES, Banerjee S, Berger PB. Perioperative management of patients with coronary stents. J Am Coll Cardiol 2007; 49: 2145-2150.
    CrossrefPubMedGoogle Scholar
  • 44 Hirsch AT, Haskal ZJ, Hertzer NR. et al. 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.
    CrossrefPubMedGoogle Scholar
  • 45 Sacco RL, Adams R, Albers G. et al. Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack. Circulation 2006; 113: e409-e449.
    PubMedGoogle Scholar
  • 46 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.
    CrossrefPubMedGoogle Scholar
  • 47 Chen ZM, Jiang LX, Chen YP. et al. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomized placebo-controlled trial. Lancet 2005; 366: 1607-1621.
    CrossrefPubMedGoogle Scholar
  • 48 Sabatine MS, Cannon CP, Gibson CM. et al. CLARITY-TIMI 28 Investigators. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med 2005; 352: 1179-1189.
    PubMedGoogle Scholar
  • 49 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.
    CrossrefPubMedGoogle Scholar
  • 50 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.
    PubMedGoogle Scholar
  • 51 Bhatt DL, Topol EJ. Scientific and therapeutic advances in antiplatelet therapy. Nat Rev Drug Discov 2003; 02: 15-28.
    CrossrefPubMedGoogle Scholar
  • 52 Coller BS. Anti-GPIIb-IIIa drugs: current strategies and future directions. Thromb Haemost 2001; 86: 427-443.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 53 Koscielny J, Ziemer S, Radtke H. et al. A practical concept for preoperative identification of patients with impaired primary hemostasis. Clin Appl Thromb 2004; 10: 195-204.
    PubMedGoogle Scholar
  • 54 Wisloff Godall HC. Prolonged bleeding time with adequate platelet count in hospital patients. Scand J Haematol 1981; 27: 45-50.
    PubMedGoogle Scholar
  • 55 Rodgers RP, Levin J. A critical reappraisal of the bleeding time. Semin Thromb Hemost 1990; 16: 1-20.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 56 Lind SE. The bleeding time does not predict surgical bleeding. Blood 1991; 77: 3547-3552.
    PubMedGoogle Scholar
  • 57 Scharf RE. In vitro thromboxane synthesis of depleted platelets following renal transplantation. Thromb Haemost 1990; 64: 161-164.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 58 Scharf RE, Hoffmann T, Kirchhoff EM, Kelm M. Unpublished observations. 2010
    PubMedGoogle Scholar
  • 59 Sugidachi A, Ogawa T, Kurihara A. et al. The grater 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; 05: 1545-1551.
    CrossrefPubMedGoogle Scholar
  • 60 Cattaneo M. New P2Y12 blockers. J Thromb Haemost 2009; 07 (Suppl. 01) 262-265.
    CrossrefPubMedGoogle Scholar
  • 61 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: 2001-2015.
    PubMedGoogle Scholar
  • 62 Harrington RA, Stone GW, McNulty S. et al. Platelet inhibition with cangrelor in patients undergoing PCI. N Engl J Med 2009; 361: 2318-2329.
    CrossrefPubMedGoogle Scholar
  • 63 Bhatt DL, Lincoff AM, Gibson M. et al. Intravenous platelet blockade with cangrelor during PCI. N Engl J Med 2009; 361: 2330-2341.
    CrossrefPubMedGoogle Scholar
  • 64 Kastrati A, Ndrepepa G. Cangrelor – a champion lost in translation? N Engl J Med. 2009; 361: 2382-2384.
    PubMedGoogle Scholar
  • 65 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: 1045-1057.
    PubMedGoogle Scholar
  • 66 Schömig A. Ticagrelor – is there need for a new player in the antiplatelet-therapy field? N Engl J Med. 2009; 361: 1108-1111.
    PubMedGoogle Scholar
  • 67 George JN, Shattil SJ. The clinical importance of acquired abnormalities of platelet function. N Engl J Med 1991; 324: 27-39.
    CrossrefPubMedGoogle Scholar
  • 68 Steering Committee 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.
    CrossrefPubMedGoogle Scholar
  • 69 Patrono C, Coller BS, FitzGerald GA. et al. Plateletactive drugs: the relationship among dose, effectiveness, and side effects. The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126: 234S-264S.
    PubMedGoogle Scholar
  • 70 Scharf RE. Congenital and acquired platelet function disorders. Hämostaseologie 2003; 23: 170-180.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 71 Bhatt DL. Intensifying platelet inhibition – navigating between Scylla and Charybdis. N Engl J Med 2007; 357: 2078-2081.
    CrossrefPubMedGoogle Scholar
  • 72 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.
    CrossrefPubMedGoogle Scholar
  • 73 Ridker PM, Cook NR, Lee I-M. et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med 2005; 352: 1293-1304.
    CrossrefPubMedGoogle Scholar
  • 74 Rothwell PM. External validity of randomized controlled trials: ‘to whom do the results of this trial apply’?. Lancet 2005; 365: 82-93.
    CrossrefPubMedGoogle Scholar
  • 75 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.
    CrossrefPubMedGoogle Scholar
  • 76 Levi M. Epidemiology and management of bleeding in patients using vitamin K antagonists. J Thromb Haemost 2009; 07 (Suppl. 01) 103-106.
    CrossrefPubMedGoogle Scholar
  • 77 Greaves M, Watson HG. Approach to the diagnosis and management of mild bleeding disorders. J Thromb Haemost 2007; 05 (Suppl. 01) 167-174.
    CrossrefPubMedGoogle Scholar
  • 78 Zotz RB, Scharf RE. Recombinant factor VIIa in patients with platelet function disorders or thrombocytopenia. Hämostaseologie 2007; 27: 251-262.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 79 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.
    CrossrefPubMedGoogle Scholar
  • 80 Mannuci PM. Desmopressin (DDAVP) in the treatment of bleeding disorders: the first 20 years. Blood 1997; 90: 2515-2521.
    PubMedGoogle Scholar