Antikoagulation bei pulmonal arterieller Hypertonie

Zusammenfassung

Die pulmonal arterielle Hypertonie (PAH) wird häufig von Thrombose und Thromboembolien vorzugsweise der kleinen Lungenarteriolen begleitet. Diese sind eine Folge der endothelialen Dysfunktion v. a. der kleinen Pulmonalarteriolen, die mit einer prothrombotischen und verminderten antifibrinolytischer Aktivität einhergeht. Auch die Funktion der Blutplättchen ist gestört. Zudem haben die meisten Patienten mit PAH eine Rechtsherzinsuffizienz mit vergrößertem rechten Ventrikel und verlangsamten Blutfluss. Neben diesen pathopysiologischen Befunden begründen vier nicht randomisierte klinische Studien, die eine verbesserte Prognose durch die Therapie mit Marcumar vermuten lassen, die Rationale zur Antikoagulation bei PAH. In diesem Übersichtsartikel sollen die wichtigsten Studien zur Antikoagulation bei PAH sowie die derzeitigen Empfehlungen aus den Leitlinien zusammengefasst werden.

Summary

In pulmonary arterial hypertension (PAH), thrombosis and thromboembolism occurs as a consequence of pulmonary microvasculopathy with a change of pulmonary vascular microenviroment toward a procoagulant, prothrombotic and antifibrinolytic pattern. Circulating antiphospholipid antibodies, increased plasma levels of platelet aggregating agents (serotonin, thromboxane), adhesion molecules (P selectin, von Willebrand factor), antifibrinolytic enzymes (plasminogen activator inhibitor 1) and prothrombotic cytokines have been identified in PAH patients so far. Thrombogenic pulmonary vasculopathy has been documented in many patients with PAH. Furthermore, most patients will not be diagnosed until right heart enlargement and impaired right ventricular function has developed. Thus, there is clear rationale for a treatment with anticoagulation. In four uncontrolled studies Warfarin improved the prognosis of patients with idiopathic and other forms of PAH. However, so far there are no prospective randomised studies evaluating the role of anticoagulants in the treatment of PAH. This review summarizes the current data and guidelines concerning anticoagulation in PAH.

Schlüsselwörter

Endotheliale Dysfunktion - Rechtsherzinsuffizienz - pulmonale Hypertonie - Blutgerinnung

Keywords

Endothelial dysfunction - right heart failure - pulmonary hypertension

• Literatur

• 1 Ahnert AM, Freudenberger RS. What do we know about anticoagulation in patients with heart failure?. Curr Opin Cadiol 2008; 23: 228-232.
• 2 Archer S, Rich S. Primary pulmonary hypertension: a vascular biology and translational tresearch, work in progress. Circulation 2000; 102: 2781-2791.
• 3 Badesch DB, Abman SH, Simonneau G. et al. Medical therapy for pulmonary arterial hypertension. Updated ACCP Evidence-based clinical practice guidelines. Chest 2007; 131: 1917-1928.
• 4 Bjornson J, Edwards WD. Primary pulmonary hypertension: a histopathologic study of 80 cases. Mayo Clin Proc 1985; 60: 16-25.
• 5 Boyer-Neumann C, Brenot F, Wolf M. et al. Continuous infusion of prostacyclin decreases plasma levels of t-PA and PAI-1 in primary pulmonary hypertension. Thromb Haemost 1995; 73: 735-736.
• 6 Cacoub P, Karmochkine M, Dorent R. et al. Plasma levels of thrombomodulin in pulmonary hypertension. Am J Med 1996; 101: 160-164.
• 7 Cella G, Bellotto F, Tona F. et al. Plasma markers of endothelial dysfunction in pulmonary hypertension. Chest 2001; 120: 1226-1230.
• 8 Christman BW, MCPershon CD, Newman JH. et al. An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N Engl J Med 1992; 327: 70-75.
• 9 Cox CP, Linden J, Said SI. et al. VIP elevates cyclic AMP (cAMP) levels and inhibits in vitro platelet activation induced by platelet-activating factor (PAF). Peptides 1984; 5: 325-328.
• 10 D’Alonzo GE, Barst RJ, Ayres SM. et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med 1991; 115: 343-349.
• 11 Duchini A, Sessoms SL. Gastrointestinal hemorrhage in patients with systemic sclerosis and CREST syndrome. Am J Gastroenterol 1998; 93: 1453-1456.
• 12 Edwards BS, Weir EK, Edwards WD. et al. Coexistant pulmonary and portal hypertension: morphologic and clinical features. J Am Coll Cardiol 1987; 10: 1233-1238.
• 13 Farber HW, Loscalzo J. Pulmonary arterial hypertension. N Engl J Med 2004; 351: 1655-1665.
• 14 Frank H, Mlczoch J, Huber K. et al. The effect of anticoagulation therapie and anorectic drug-induced pulmonary hypertension. Chest 1997; 112: 714-721.
• 15 Friedman R, Mears JG, Barst RJ. Continuous infusion of prostacyclin normalizes plasma markers of endothelial cell injury and platelet aggregation in primary pulmonary hypertension. Circulation 1997; 96: 2782-2784.
• 16 Fuster V, Steele PM, Edwards WD. et al. Primary pulmonary hypertension: natural history and the importance of thrombosis. Circulation 1984; 70: 580-587.
• 17 Fuster V, Stelle PM, Edwards WD. et al. Primary pulmonary hypertension: natural history and the importance of thrombosis. Circulation 1994; 70: 580-587.
• 18 Giaid A, Saleh D. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med 1995; 333: 214-221.
• 19 Giaid A, Yanagisawa M, Langleben D. et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med 1993; 328: 1732-1739.
• 20 Gray AJ, Bishop JE, Lever MJ. et al. A putative role for fibrin(ogen) cleavage products and thrombin as mediators of vascular remodelling. Eur Resp Rev 1993; 3: 650-654.
• 21 Grünig E, Benz A, Mereles D. et al. Prognostic value of serial assessment in familial screening in patients with dilated cardiomyopathy. Eur J Heart Failure 2003; 5: 55-62.
• 22 Heimark LD, Wienkers L, Kunze K. et al. The mechanism of the interaction between amiodorone and warfarin in humans. Clin Pharmacol Ther 1992; 51: 398-407.
• 23 Hervé P, Humbert M, Sitbon O. et al. Pathobiology of pulmonary hypertension: the role of platelets and thrombosis. Clin Chaest Med 2001; 22: 451-458.
• 24 Hervé P, Launay JM, Scobohaci ML. et al. Primary pulmonary hypertension in a patient with a familial platelet storage pool disease: role of serotonin. Am J Med 1990; 89: 117-120.
• 25 Hervé P, Launay JM, Scrobohaci ML. et al. Increased plasma serotonin in primary pulmonary hypertension. Am J Med 1995; 99: 249-254.
• 26 Hoeper MM, Markevych I, Spiekerkoetter E. et al. Goal-oriented treatment and combination therapy for pulmonary arterial hypertension. Eur Respir J 2005; 26: 858-863.
• 27 Hoeper MM, Sosada M, Fabel H. Plasma coagulation profiles in patients with severe primary pulmonary hypertension. Eur Respir J 1998; 12: 1446-1449.
• 28 Huber K, Beckmann R, Frank H. et al. Fibrinogen, t-PA, and PAI-1 plasma levels in patients with pulmonary hypertension. Am J Respir Crit Care Med 1994; 150: 929-933.
• 29 Humbert M, Sitbon O, Chaouat A. et al. Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med 2006; 173: 1023-1030.
• 30 Israel DS, Stotka J, Rock W. et al. Effect of ciprofloxacin on warfarin. Clin Infect Dis 1996; 22: 251-256.
• 31 Johnson SR, Granton JT, Mehta S. Thrombotic arteriopathy and anticoagulation in pulmonary hypertension. Chest 2006; 130: 545-552.
• 32 Johnson SR, Metha S, Granton JT. Anticoagulation in pulmonary arterial hypertension: a qualitative systematic review. Eur Respir J 2006; 28: 999-1004.
• 33 Kawut SM, Horn EM, Berekashvili KK. et al. New predictors of outcome in idiopathic pulmonary arterial hypertension. Am J Cardiol 2005; 95: 199-203.
• 34 Lee SL, Wang WW, Lanzillo JJ. et al. Serotonin produces both hyperplasia and hypertrophy of bovine pulmonary artery smooth muscle cells in cukture. Am J Physiol 1994; 266: 46-52.
• 35 Loewe B, Grafe K, Ufer C. et al. Anxiety and depression in patients with pulmonary hypertension. Psychosom Med 2004; 66: 831-836.
• 36 Lopes AA, Maeda NY. Circulating von Willebrand factor antigen as a predictor of short term prognosis in pulmonary hypertension. Chest 1998; 114: 1276-1282.
• 37 McGoon M, Guttermann D, Steen V. et al. Screening, early detection, and diagnosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest 2004; 126: 14-34.
• 38 McGoon MD, Vanhoutte PM. Aggregating platelets contract isolated canine pulmonary arteries by releasing 5-hytroxytryüptamine. J Clin Invest 1984; 74: 828-833.
• 39 McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension. Circulation 2002; 106: 1477-1482.
• 40 Mereles D, Ehlken N, Kreuscher S. et al. Exercise and respiratory training improve exercise capacity and quality of life in patients with severe chronic pulmonary hypertension. Circulation 2006; 114: 1482-1489.
• 41 Moncada S, Higgs EA. Endogenous nitric oxide: physiology, pathology and clinical relevance. Eur J Clin Invest 1991; 21: 361-374.
• 42 Murphy LM, Hood EH. Bosentan and warfarin interaction. Ann Pharmacother 2003; 37: 1028-1031.
• 43 O’Reilly RA. The stereoselective interaction of warfarin and metronidazole in man. N Engl J Med 1976; 295: 345-357.
• 44 Ogata M, Ohe M, Shirato K. et al. Effects of a combination therapy of anticoagulant and vasodilator on the long-term prognosis of primary pulmonary hypertension. Jpn Circ J 1993; 57: 63-69.
• 45 Ogawa A, Matsubara H, Fujio H. et al. Risk of alveolar hemorrhage in patients with primary pulmonary hypertension – anticoagulation and epoprostenol therapy. Circ J 2005; 69: 216-220.
• 46 Olschewski H, Hoeper MM, Borst MM. et al. Diagnosis and therapy of chronic pulmonary hypertension. Clin Res Cardiol 2007; 96: 301-330.
• 47 Olschewski H, Seeger W. (Hrsg). Pulmonale Hypertonie. Bremen: Uni-Med; 2000
• 48 Petkov V, Musgeoller W, Ziesche R. et al. Vasoactive intestinal peptide as a new drug for treatment of primary pulmonary hypertension. J Clin Invest 2003; 111: 1339-1346.
• 49 Priskorn M, Sidhu JS, Larsen F. et al. Investigation of multiple dose citalopram on the pharmacokinetics and pharmacodynamics of racemic warfarin. Br J Clin Pharmacol 1997; 44: 199-202.
• 50 Rich S, Kaufmann E, Levy PS. The effect of high-doses of calcium-channel blockers on survival in primary pulmonary hypertension. N Engl J Med 1992; 327: 76-81.
• 51 Robbins IM, Kawut SM, Yung D. et al. A study of aspirin and clopidogrel in idiopathic pulmonary arterial hypertension. Eur Resp J 2006; 27: 578-584.
• 52 Samaki F, Kyotani S, Nagaya N. et al. Increased plasma p-selectin and decreased thrombomodulin in pulmonary arterial hypertension were improved by continuous prostacyclin therapy. Circulation 2000; 102: 2720-2725.
• 53 Simonneau G, Galie N, Rubin LJ. et al. Clinical classification of pulmonary hypertension. JAm Coll Cardiol 2004; 43: 5-12.
• 54 Sitbon O, McLaughlin VV, Badesch DB. et al. Survival in patients with class III idiopathic pulmonary arterial hypertension treated with first line oral bosentan compared with an historical cohort of patients started on intravenous epoprostenol. Thorax 2005; 60: 1025-1030.
• 55 Veyradier A, Nishikubo T, Humbert M. et al. Improvement of von Willebrand factor proteolysis after prostacyclin infusion in severe pulmonary arteriel hypertension. Circulation 2000; 102: 2460-2462.
• 56 Wagenvoort CA. Lung biopsi specimens in the evaluation of pulmonary vascular disease. Chest 1980; 77: 614-625.
• 57 Wagenvoort CA, Mulder PG. Thrombotic lesions in primary plexogenic arteriopathy: similar patghogeneis or complication?. Chest 1993; 103: 844-849.
• 58 Wagenvoort CA. Morphological substrate for the reversibility and irreversibility of pulmonary hypertension. Eur Heart J 1988; 9: 7-12.
• 59 Weibert RT, Lorentz SM, Townsend RJ. et al. Effect of erythromycin in patients receiving long-term warfarin therapy. Clin Pharm 1989; 8: 210-214.
• 60 Welsch CH, Hassell KL, Badesch DB. et al. Coagulation and fibrinolytic profiles in patients with severe pulmonary hypertension. Chest 1996; 110: 710-717.
• 61 Whittle BJR, Moncada S, Vane JR. Comparison of the effects of prostacyclin (PGI2), prostaglandin E1 and D2 on platelet aggregation in different species. Prostaglandins 1978; 16: 373-388.
• 62 Widlitz AC, Barst RJ, Horn EM. Sitaxsentan: a novel endothelin-A receptor antagonist for pulmonary arterial hypertension. Expert Rev Cardiovasc Ther 2005; 3: 985-991.