Chronisch-arterielle Verschlusskrankheit der Beine im Stadium IIb-IV

Zusammenfassung

Die Faktor-V- und Faktor-II-Mutationen sind nach der Literatur mit einem erhöhten Risiko für venöse Thrombosen verbunden. Die Bedeutung der Mutationen im Faktor-IIund -V-Gen für die Entstehung und das Fortschreiten der arteriellen Verschlusskrankheit ist bislang nicht geklärt. Wir untersuchten das Vorhandensein dieser Mutationen bei 152 Patienten mit dokumentierter pAVK und 318 Kontrollen (ohne pAVK) mittels Polymerase-Kettenreaktion (PCR) und RFLP-Analyse. Die Ergebnisse erbrachten keinen Hinweis auf eine Assoziation zwischen einer Faktor-II-Mutation und der Entstehung einer pAVK. Dagegen waren Faktor- V-Mutationen bei pAVK-Patienten doppelt so häufig zu beobachten wie bei Gesunden (in der Kontrollgruppe ergaben sich 12 positive Fälle bei 318 Probanden, in der Patientengruppe ergaben sich 12 positive Fälle bei 152 Patienten). In der statistischen Analyse wurde das Signifikanzniveau (p = 0,05) zwar erreicht, aber nicht unterschritten. Das Chancenverhältnis (Odds-Ratio) betrug 2,19 (Konfidenzintervall 0,96-4,99). Schlussfolgerung: Die biologische Relevanz der Faktor-V-Mutation in der Pathogenese der pAVK kann aufgrund unserer Daten diskutiert werden.

Summary

Mutations in factor-V- and factor-II-genes are correlated with an increased risk for venous thrombosis according to the literature. The significance of the mutations in factor- II- and factor-V-genes for the development of the peripheral arterial occlusive disease is not known. Therefore, we investigated the presence of these mutations in 152 patients with documented peripheral arterial occlusive disease and 318 controls without peripheral arterial occlusive disease with polymerase chain reaction (PCR).

There was no association between factor-II-mutation and peripheral arterial occlusive disease. The factor-V-mutation, however, was increased in patients with peripheral arterial occlusive disease double fold (12 positive cases in 318 controls, 12 positive cases in 152 patients with peripheral arterial occlusive disease). The significance level was reached (p = 0.05) in statistical analysis but the result did not fall below the significance level as necessary to reach statistical significance (odds ratio 2.19). Nevertheless, from these data we have to discuss a biological relevance of factor-V-mutation in the pathogenesis of peripheral arterial occlusive disease.

Schlüsselwörter

pAVK - Mutation im Faktor-II-Gen - Mutation im Faktor- V-Gen

Keywords

pAOD - mutation in factor-II-gene - mutation in factor-V-gene

• Literatur

• 1 Albucher JF, Guiraud-Chaumeil B, Chollet F. et al. Frequency of resistance to activated protein S due to factor V mutation in young patients with ischemic stroke. Stroke 1996; 27: 766.
• 2 Ardissino D, Peyvandi F, Merlini PA. et al. Factor V (Arg506 to Gln) mutation in young survivors of myocardial infarction. Thromb Haemost 1996; 75: 701-2.
• 3 Bertina RM, Koeleman BP, Koster T. et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-7.
• 4 Catto A, Carter A, Ireland H. et al. Factor V Leiden gene mutation and thrombin generation in relation to acute stroke. Arteriscler Thromb Vasc Biol 1995; 15: 783-5.
• 5 Cushman M, Rosendaal FR, Psaty BM. et al. Factor V Leiden ist not a risk factor for arterial vascular disease in the elderly: results form the Cardiovascular Health Study. Thromb Haemost 1998; 79: 912-5.
• 6 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 S. Proc Natl Acad Sci USA 1993; 90: 1004-8.
• 7 De Lucia D, Cerbone AM, Belli A. et al. Resistance to activated protein C in adults with a history of juvenile transient ischemic attacks. Thromb Haemost 1996; 76: 627-31.
• 8 De Stefano V, Chiusolo P, Paciaroni K. et al. Prothrombin G20210A mutant genotype is a risk factor for cerebrovascular ischemic disease in young patients. Blood 1998; 91: 3362-5.
• 9 Doggen CJM, Cats VM, Bertina RM. et al. Interaction of coagulation defects and cardiovascular risk factor. Increased risk of myocardial infarction associated with factor V Leiden or prothrombin 20210A. Circulation 1998; 97: 1037-41.
• 10 Emmerich J, Poirier I, Evans A. et al. Myocardial infarction, Arg 506 to Gln Factor V mutation, and activated protein C resistance (Letter). Lancet 1995; 45: 321.
• 11 Ferraresi P, Marchetti G, Legnani C. et al. The heterozygous 20210 G/A prothrombin genotype is associated with early venous thrombophilias and is not increased in frequency in arterial disease. Arterioscler Thromb Vasc Biol 1997; 17: 2418-22.
• 12 Fisher M, Fernandez JA, Amerisco SF. et al. Activated protein C resistance in ischemic stroke not due to factor V arginine 506 O glutamine mutation. Stroke 1996; 27: 1163-6.
• 13 Foley PW, Irvine CD, Standen GR. et al. Activated protein C resistance, factor V Leiden and peripheral vascular disease. Cardiovasc Surg 1997; 5: 157-60.
• 14 Inbal A, Freimark D, Modan B. et al. Synergistic effects of prothrombotic polymorphisms and atherogenic factors on the risk of myocardial infarction. Blood 1999; 93: 2186-90.
• 15 Irvine CD, Foley PW, Standen GR. et al. Should patients with atherosclerosis of peripheral vascular disease be stratified for factor V Leiden?. Blood 1997; 90: 211-4.
• 16 Kiechl S, Muigg A, Santer P. et al. Poor response to activated protein C as a prominent risk predictor of advanced arterial disease. Circulation 1999; 99: 641-9.
• 17 Longstreth WT, Rosendaal FR, Siscovick DS. et al. Risk of stroke in young women and two prothrombotic mutations: factor V Leiden and prothrombin gene variant (G20210A). Stroke 1998; 29: 577-80.
• 18 Poort SR, Rosendaal FR, Reitsma PH. et al. A common genetic variation in the 3’-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996; 88: 3698-703.
• 19 Renner W, Koppen H, Brodmann M. Factor II G20210A and factor V G1691A gene mutations and peripheral arterial occlusive disease. Thromb Haemost 2000; 83: 20-2.
• 20 Ridker PM, Hennenkens CH, Lindpaintner K. et al. Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction. N Engl J Med 1995; 332: 912-7.
• 21 Ridker PM, Hennenkens CH, Miletich JP. G20210A mutation in prothrombin gene and risk of myocardial infarction, stroke, and venous thrombosis in a large cohort of US men. Circuclation 1999; 99: 999-1004.
• 22 Ripoll L, Paulin D, Thomas S. et al. Multiplex PCR-mediated site-directed mutagenesis for onestep determination of factor V Leiden and G20210A transition of the prothrombin gene. Thromb Haemost 1997; 78: 960-1.
• 23 Rosendaal FR, Siscovick DS, Schwartz SM. et al. Factor V Leiden (resistance to activated protein C) increases the risk of myocardial infarction in young women. Blood 1997; 89: 2817-21.
• 24 Rosendaal FR, Siscovick DS, Schwartz SM. et al. A common prothrombin variant (20210 G to A) increases the risk of myocardial infarction in young women. Blood 1997; 90: 1747-50.
• 25 Rosenberg RD, Aird WC. Thrombosis. In: Haber E. (ed). Molecular Cardiovascular Medicine. New York: Scientific American; 1995: 155-32.
• 26 Sampram ES, Lindblad B, Dahlbäck B. Activated Protein C resistance in patients with peripheral vascular disease. J Vasc Surg 1998; 28: 624-9.