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DOI: 10.1055/s-0037-1619596
Venöse Thrombose und Thrombophilie
Management von Prophylaxe und TherapieVenous thrombosis and thrombophilia: management of prophylaxis and therapyPublication History
Publication Date:
20 January 2018 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00034925/200304/lookinside/thumbnails/10-1055-s-0037-1619596_de-1.jpg)
Zusammenfassung
In den Industrieländern wird die Mortalitätsstatistik von kardiovaskulären Erkrankungen angeführt, wovon wesentliche Anteile auf venöse Thrombose und Thromboembolie fallen. Ursache einer Thrombose können temporäre Faktoren oder eine permanente thrombophile Diathese sein. Neue Erkenntnisse über die Pathophysiologie der Thrombose sowie neue diagnostische Methoden erleichtern die Erstellung eines Risikoprofils bezüglich venöser Thrombosen. Im Folgenden sollen verschiedene Thrombophilierisikofaktoren hinsichtlich ihrer Bedeutung und Diagnostik beschrieben und diskutiert werden. Weiterhin soll ausgeführt werden, welche prophylaktischen und therapeutischen Maßnahmen bei Thrombophiliekonstellation oder manifester Thrombose vorzunehmen sind. Hierbei wird auf zurzeit zugelassene, aber auch auf vor der Zulassung stehende neue Antikoagulanzien eingegangen (Pentasaccharid, Melagatran), deren Verwendung eine zunehmend patientenfreundliche und kosteneffiziente Prophylaxe und Behandlung venöser thromboembolischer Komplikationen verspricht.
Abstract
Cardiovascular disease, to which venous thrombosis and pulmonary embolism contribute a major part, are the leading cause of death in industrialized countries. Thrombosis is caused by temporary risk factors or by thrombophilia. Increasing knowledge concerning the pathophysiology of thrombosis and new diagnostic tools allow a thrombotic risk assessment. In this paper thrombotic risk factors will be discussed with respect to their significance and diagnosis as well as methods of prophylaxis and treatment for patients at risk for or with diagnosed thrombosis. Furthermore, currently available as well as new anticoagulants (pentasaccharide, melagatran) will be discussed and their potential for patient-oriented and cost-efficient prophylaxis and treatment of thromboembolic complications outlined.
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Literatur
- 1 Agnelli G, Prandoni P, Santamaria MG. et al. Warfarin Optimal Duration Italian Trial Investigators. Three months versus one year of oral anticoagulant therapy for idiopathic deep venous thrombosis. New Engl J Med 2001; 345: 165-9.
- 2 Anderson FA, Wheeler HB, Goldberg RJ. et al. A population based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. Arch Intern Med 1991; 151: 933-8.
- 3 Aschwanden M, Labs KH, Engel H. et al. Acute deep vein thrombosis: early mobilization does not increase the frequency of pulmonary embolism. Thromb Haemost 2001; 85: 42-6.
- 4 Ballem P. Acquired thrombophilia in pregnancy. Semin Thromb Hemost 1998; 24 (Suppl. 01) 41-7.
- 5 Bauer KA, Eriksson BI, Lassen MR. et al. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery. N Engl J Med 2001; 345: 1305-10.
- 6 Bertina RM, Koeleman RPC, Koster T. et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-7.
- 7 Bick RL, Jakway J, Baker Jr WF. Deep vein thrombosis: prevalence of etiologic factors and results of management in 100 consecutive patients. Semin Thromb Hemost 1992; 18: 267-74.
- 8 Brattstrom L. Vitamins as homocysteine-lowering agents. J Nutr 1996; 126 (Suppl. 04) 1276-80.
- 9 Caprini JA, Arcelus JI, Reyna JJ. Effective risk stratification of surgical and nonsurgical patients for venous thromboembolic disease. Semin Hematol 2001; 38: 12-9.
- 10 Cattaneo M. Hyperhomocysteinaemia, atherosclerosis and thrombosis. Thromb Haemost 1999; 81: 165-76.
- 11 Cattaneo M, Lombardi R, Lecchi A. et al. Low plasma levels of vitamin B6 are independently associated with a heightened risk of deep-vein thrombosis. Circulation 2001; 104: 2442-6.
- 12 Chan WP, Lee CK, Kwong YL. et al. A novel mutation of ARG306 of factor V-gene in Hong Kong chinese. Blood 1998; 91: 1135-9.
- 13 Clagett GP. Prevention of postoperative venous thromboembolism: an update. Am J Surg 1994; 168: 515-22.
- 14 Clagett GP, Anderson Jr FA, Geerts WA. et al. Prevention of venous thromboembolism. Chest 1998; 114 (Suppl. 05) 531-60.
- 15 Collet JP, Montalescot G, Choussat R. et al. Enoxaparin in unstable angina patients with renal failure. Int J Cardiol 2001; 80: 81-2.
- 16 Collins R, Scrimgeour A, Yusuf S. et al. Reduction in fatal pulmonary embolism and venous thrombosis by perioperative administration of subcutaneous heparin. Overview of results of randomized trials in general, orthopedic, and urologic surgery. N Engl J Med 1988; 318: 1162-73.
- 17 Consensus statement. Prevention of venous thromboembolism. Intern Angiol 1997; 16: 3-38.
- 18 Dahlbäck B, Carlsson M, Svensson PJ. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C. Proc Natl Acad Sci USA 1993; 90: 1004-8.
- 19 Daly E, Vessey MP, Hawkins MM. et al. Risk of venous thromboembolism in users of hormone replacement therapy. Lancet 1996; 348: 977-80.
- 20 Deutsche Gesellschaft für Angiologie. Leitlinien zur Diagnostik und Therapie der Venenthrombose und Lungenembolie. Vasa 2002; 31: 3-19.
- 21 Dyke CK, Becker RC, Kleiman NS. et al. First experience with direct factor Xa inhibition in patients with stable coronary disease: a pharmacokinetic and pharmacodynamic evaluation. Circulation 2002; 105: 2385-91.
- 22 Eldor A. Thrombophilia, thrombosis and pregnancy. Thromb Haemost 2001; 86: 104-11.
- 23 Eriksson H, Wahlander K, Lundström T. et al for the Thrive III Investigators. Extended secondary prevention with the oral direct thrombin inhibitor ximelagatran for 18 months after 6 months of anticoagulation in patients with venous thromboembolism: a randomized, placebo-controlled trial. Thromb Haemost 2003; 1 (Suppl. 01) OC005.
- 24 Falcon CR, Cattaneo M, Panzeri D. et al. High prevalence of hyperhomocyst(e)inemia in patients with juvenile venous thrombosis. Arterioscl Thromb 1994; 14: 1080-3.
- 25 Fletcher SW, Colditz GA. Failure of estrogen plus progestin therapy for prevention. JAMA 2002; 288: 366-8.
- 26 Frosst P, Blom HJ, Milos R. et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995; 10: 111-3.
- 27 Gibbs NM. Venous thrombosis of the lower limbs with particular reference to bed rest. Br J Surg 1957; 45: 477-82.
- 28 Ginsberg JH, Hirsh J. Use of antithrombotic agents during pregnancy. Chest 1998; 114 (Suppl. 05) 524S-30S.
- 29 Ginsberg JS, Wells PS, Brill-Edwards P. et al. Antiphospholipid antibodies and venous thromboembolism. Blood 1995; 86: 3685-91.
- 30 Goldhaber S. Epidemiology of pulmonary embolism and deep venous thrombosis. Haemost Thromb 1993; 1327-33.
- 31 Gould MK, Dembitzer AD, Doyle RL. et al. Low-molecular-weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis. A meta-analysis of randomized, controlled trials. Ann Intern Med 1999; 130: 800-9.
- 32 Gould MK, Dembitzer AD, Sanders GD. et al. Low-molecular weight heparins compared with unfractionated heparin for treatment of acute deep vein thrombosis. A cost-effectiveness analysis. Ann Intern Med 1999; 130: 789-99.
- 33 Greaves M, Cohen H, MacHin SJ. et al. Guidelines on the investigation and management of the antiphospholipid syndrome. Br J Haematol 2000; 109: 704-15.
- 34 Gresele P, Agnelli G. Novel approaches to the treatment of thrombosis. Trends Pharmacol Sci 2002; 23: 25-33.
- 35 Griffin JH, Evatt B, Wideman C. et al. Anticoagulant protein C pathway defective in a majority of thrombophilic patients. Blood 1993; 92: 1989-93.
- 36 Gurwitz JH, Avorn J, Ross-Degnan D. et al. Aging and the anticoagulant response to warfarin therapy. Ann Intern Med 1992; 116: 901-4.
- 37 Haas SK. Venous thromboembolic risk and its prevention in hospitalized medical patients. Semin Thromb Hemost 2002; 28: 577-84.
- 38 Halperin JL. for the SPORTIF III Investigators. Präsentation im Rahmen der ‘late-breaking clinical trials’. 52nd Annual Session of the American College of Cardiology. April 2003. Chicago/USA.:
- 39 Harenberg J, Schneider D, Heilmann L. et al. Lack of anti-factor Xa activity in umbilical cord vein samples after subcutaneous administration of heparin or low molecular weight mass heparin in pregnant women. Haemostasis 1993; 23: 314-20.
- 40 Hassel KL. Altered hemostasis in pulmonary hypertension. Blood Coagul Fibrinol 1998; 9: 107-17.
- 41 Haverkate F, Samama M. Familial dysfibrinogenemia and thrombophilia. Report on a study of the SSC subcommitte on fibrinogen. Thromb Haemost 1995; 151-61.
- 42 Heit JA, Colwell CW, Francis CW. et al. Astra-Zeneca Arthroplasty Study Group. Comparison of the oral direct thrombin inhibitor ximelagatran with enoxaparin as prophylaxis against venous thromboembolism after total knee replacement: a phase 2 dose-finding study. Arch Intern Med 2001; 161: 2215-21.
- 43 Hirsh J, Hull RD, Raskob GE. Epidemiology and pathogenesis of venous thrombosis. J Am Coll Cardiol 1986; 8: 104B-13B.
- 44 Hirsh J, Warkentin TE, Hirsh J. et al. Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. Chest 2001; 119: 64S-94S.
- 45 Huisman MV. on behalf of The THRIVE II&V Investigators. Efficacy and safety of the oral direct thrombin inhibitor ximelagatran compared with current standard therapy for acute symptomatic deep vein thrombosis, with or without pulmonary embolism: a randomized, double-blind, multinational study. Thromb Haemost 2003; 1 (Suppl. 01) OC003.
- 46 Hull RD, Raskob GE, Hirsh J. et al. Continous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal-vein thrombosis. N Engl J Med 1986; 315: 1109-14.
- 47 Hull R, Hirsh J, Jay R. et al. Different intensities of oral anticoagulant therapy in the treatment of proximal-vein thrombosis. N Engl J Med 1982; 307: 1676-81.
- 48 Hull R, Raskob G, Pineo G. et al. A comparison of subcutaneous low-molecular-weight heparin with warfarin sodium for prophylaxis against deep-vein thrombosis hip or knee implantation. N Engl J Med 1993; 329: 1370-6.
- 49 Jordan WM. Pulmonary embolism. Lancet 1961; 8: 1146-7.
- 50 Kearon C, Gent M, Hirsh J. et al. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med 1999; 340: 901-7.
- 51 Khamashta MA, Cudtrado MJ, Mujic F. et al. The management of thrombosis in the antiphospholipid-antibody syndrome. N Engl J Med 1995; 332: 993-7.
- 52 Kirchhof B, Palmer AJ, Kakkar VV. et al. Langzeitfolgen der tiefen Beinvenenthrombose: ihre wirtschaftliche Bedeutung. Gesundheitsökon Qualitätsman 1997; 2: 40-4.
- 53 Kniffin WD, Baron JA, Barrett J. et al. The epidemiology of diagnosed pulmonary embolism and deep vein thrombosis in the elderly. Arch Int Med 1994; 154: 861-6.
- 54 Koster T, Rosendaal FR, Reitsma PH. et al. Factor VII and fibrinogen levels as risk factors for venous thrombosis. Thromb Haemost 1994; 71: 719-22.
- 55 Kyrle PA, Minar E, Hirschl M. et al. High plasma levels of factor VIII and the risk of recurrent venous thromboembolism. N Engl J Med 2000; 343: 457-62.
- 56 Lane AD, Mannucci PM, Bauer AK. et al. Inherited thrombophilia: part 1. Thromb Haemost 1996; 76: 651-62.
- 57 Lassen MR, Borris LC, Anderson BS. et al. Efficacy and safety of prolonged thromboprophylaxis with a low molecular weight heparin (dalteparin) after total hip arthroplasty – the Danish Prolonged Prophylaxis (DaPP) Study. Thromb Res 1998; 15: 281-7.
- 58 Lensing AWA, Prandoni P, Prins MH. et al. Deep-vein thrombosis. Lancet 1999; 353: 479-85.
- 59 Leroyer C, Mercier B, Oger E. et al. Prevalence of the 200210 A allele of the prothrombin gene in venous thromboembolism patients. Thromb Haemost 1998; 80: 49-51.
- 60 Lutz L, Haas S, Hach-Wunderle V. et al. Venöse Thromboembolie in der Inneren Medizin: Risikoeinschätzung und medikamentöse Prophylaxe. Med Welt 2002; 53: 231-4.
- 61 Mammen EF. Plasminogen abnormalities. Semin Thromb Hemost 1989; 9: 50-1.
- 62 Mammen EF. Pathogenesis of venous thrombosis. Chest 1992; 102: 640S-4S.
- 63 Margaglione M, Brancaccio V, Giuliani N. et al. Increased risk for venous thrombosis in carriers of the prothrombin G20210 A gene variant. Ann Intern Med 1998; 129: 89-93.
- 64 Martinelli I. Risk factors in venous thromboembolism. Thromb Haemost 2001; 86: 395-403.
- 65 Martinelli I, Bucciarelli P, Margaglione M. et al. The risk of venous thromboembolism in family members with mutations in the genes of factor V or prothrombin or both. Br J Haematol 2000; 111: 1223-9.
- 66 Meijers CMJ, Tekelenburg LHW, Bouma NB. et al. High levels of coagulation faxtor XI as a risk factor for venous thrombosis. N Engl J Med 2000; 342: 696-701.
- 67 Mismetti P, Laporte-Simitsidis S, Tardy B. et al. Prevention of venous thromboembolism in internal medicine with unfractionated or low-molecular-weight heparins: a meta-analysis of randomised clinical trials. Thromb Haemost 2000; 83: 14-9.
- 68 Moll S, Ortel TL. Monitoring warfarin therapy in patients with lupus anticoagulants. Ann Intern Med 1997; 127: 177-85.
- 69 Moser M, Ruef J, Peter K. et al. Ecarin clotting time but not aPTT correlates with PEG-hirudin plasma activity. J Thromb Thrombol 2001; 12: 165-9.
- 70 Mousa SA. Anticoagulants in thrombosis and cancer: the missing link. Semin Thromb Hemost 2002; 28: 45-52.
- 71 O’Brien JA, Caro JJ. Direct medical cost of managing deep vein thrombosis according to the occurrence of complications. Pharmacoeconomics 2002; 20: 603-15.
- 72 Palmer AJ, Koppenhagen K, Kirchhof B. et al. Efficacy and safety of low molecular weight heparin, unfractionated heparin and warfarin for thromboembolism prophylaxis in orthopaedic surgery: a meta-analysis of randomized clinical trials. Haemostasis 1997; 27: 75-84.
- 73 Palmer AJ, Schramm W, Kirchhof B. et al. Low molecular weight heparin and unfractionated heparin for prevention of thromboembolism in general surgery: a meta-analysis of randomized clinical trials. Haemostasis 1997; 27: 65-74.
- 74 Partsch H, Blättler W. Leitlinien zur Thromboembolie-Prophylaxe.Aktualisierte Fassung. Phlebologie 2000; 29: 106-13.
- 75 Poort SR, Rosendaal FR, Reitsma PH. et al. A common genetic variation in the 3‘-untranslated region of the human prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996; 88: 3698-703.
- 76 Prandoni P, Lensing AWA, Büller HR. et al. Deep-vein thrombosis and the incidence of subsequent symptomatic cancer. N Engl J Med 1992; 327: 1128-33.
- 77 Prandoni P, Lensing AW, Cogo A. et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med 1996; 125: 1-7.
- 78 Proceedings of the American College of Chest Physicians 5th Consensus on Antithrombotic Therapy. Chest 1998; 114: 439S-769S.
- 79 Rees DC, Cox M, Clegg JB. World distribution of factor V Leiden. Lancet 1995; 346: 1133-4.
- 80 Ridker PM, Glynn RJ, Miletich JP. et al. Agespecific incidence rates of venous thromboembolism among heterozygous carriers of factor V-Leiden mutation. Ann Intern Med 1997; 126: 528-31.
- 81 Ridker PM, Goldhaber SZ, Danielson E. et al. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med 2003; 348: 1425-34.
- 82 Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet 1999; 353: 1167-73.
- 83 Rosendaal FR, Doggen CJM, Zivelin A. et al. Geographic distribution of the 20210 G to A prothrombin variant. Arterioscl Thromb Vasc Biol 1998; 18: 1287-91.
- 84 Rosendaal FR, Koster T, Vandenbroucke JP. et al. High risk of thrombosis in patients homozygous for factor V Leiden. Blood 1995; 85: 1504-8.
- 85 Ruef J, Katus HA. New antithrombotic drugs on the horizon. Expert Opin Investig Drugs 2003; 12: 781-97.
- 86 Samama MM, Cohen AT, Darmon JY. et al. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. Prophylaxis in Medical Patients with Enoxaparin Study Group. N Engl J Med 1999; 341: 793-800.
- 87 Sandler DA, Martin JF. Autopsy proven pulmonary embolism in hospital patients: are we detecting enough deep vein thrombosis?. J R Soc Med 1989; 82: 203-5.
- 88 Schulman S. The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. The Duration of Anticoagulation Trial Study Group. N Engl J Med 1997; 336: 393-8.
- 89 Schulman S, Svenungsson E, Granqvist S. Anticardiolipin-antibodies predict early recurrence of thromboembolism and death among patients with venous thromboembolism following anticoagulant therapy. Am J Med 1998; 104: 332-8.
- 90 Scurr JH, Machin SJ, Bailey-King S. et al. Frequency and prevention of symptomless deep-vein thrombosis in long-haul flights: a randomized trial. Lancet 2001; 357: 1485-9.
- 91 Shapira Y, Sagie A, Battler A. Low-molecular-weight heparin for the treatment of patients with mechanical heart valves. Clin Cardiol 2002; 25: 323-7.
- 92 Silverstein MD, Heit JA, Mohr DN. et al. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med 1999; 159: 445-53.
- 93 Simioni P, Prandoni P, Zanon E. et al. Deep venous thrombosis and lupus anticoagulant. Thromb Haemost 1996; 76: 187-9.
- 94 Simonneau G, Sors H, Charbonnier B. et al. A comparison of low-molecular-weight heparin with unfractionated heparin for acute pulmonary embolism. The THESEE Study Group. Tinzaparine ou Heparine Standard: Evaluations dans l’Embolie Pulmonaire. New Engl J Med 1997; 337: 663-9.
- 95 Sorensen HAT, Mellemkjaer L, Steffensen FH. et al. The risk of diagnosis of cancer after primary deep vein thrombosis or pulmonary embolism. N Engl J Med 1998; 338: 1169-73.
- 96 Spitzer WO, Lewis MA, Heinemann LAJ. Third generation oral contraceptives and risk of venous thromboembolic disorders: an international case-control study. Br Med J 1996; 312: 83-8.
- 97 Stein PD, Alpert JS, Bussey HI. et al. Antithrombotic therapy in patients with mechanical and biological prosthetic heart valves. Chest 2001; 119: 220S-27S.
- 98 The MATISSE Investigators. The MATISSEDVT trial, a randomized, double-blind study comparing once-daily fondaparinux (Arixtra) with the low-molecular weight heparin (LMWH) enoxaparin, twice daily, in the initial treatment of symptomatic deep-vein thrombosis (DVT). Thromb Haemost 2003; 1 (Suppl. 01) OC 332.
- 99 Thomas RH. Hypercoagulability Syndromes. Arch Int Med 2001; 161: 2433-9.
- 100 Tripodi A, Mannucci PM. Laboratory investigation of thrombophilia. Clin Chem 2001; 47: 1597-606.
- 101 van Hylckama VA, van der Linden IK, Bertina RM. et al. High levels of factor IX increase the risk of venous thrombosis. Blood 2000; 95: 3678-82.
- 102 van Tilburg HN, Rosendaal FR, Bertina RM. Thrombin activatable fibrinolysis inhibitor and the risk for deep vein thrombosis. Blood 2000; 95: 2855-9.
- 103 Veiga F, Escriba A, Maluenda MP. et al. Low molecular weight heparin (enoxaparin) versus oral anticoagulant therapy (acenocoumarol) in the long-term treatment of deep venous thrombosis in the elderly: a randomized trial. Thromb Haemost 2000; 84: 559-64.
- 104 Weitz JI. Low-molecular-weight heparins. New Engl J Med 1997; 337: 688-99.
- 105 Williamsen D, Brown K, Luddington R. et al. Factor V Cambridge: a new mutation (Arg306Thr) associated with resistance to activated protein C. Blood 1998; 91: 1140-4.
- 106 Winkler KH. Thromboembolierisiko, hormonelle Kontrazeption und Östrogensubstitution. Gynäkologe 1997; 30: 341-51.
- 107 Kleber FX, Witt C, Vogel G. et al. for the PRINCE Study Group. Randomized comparison of enoxaparin with unfractionated heparin for the prevention of venous thromboembolism in medical patients with heart failure or severe respiratory disease. Am Heart J 2003; 145: 614-21.