Download PDF
Hamostaseologie 1999; 19(02): 77-85
DOI: 10.1055/s-0038-1660383
Übersichtsarbeiten/Review Articles
Schattauer GmbH

Die hereditäre Thrombophilie

Fortschritte in der Diagnostik
Frauke Bergmann
1   Labor Keeser, Arndt & Partner, Hamburg
,
L. Kochhan
1   Labor Keeser, Arndt & Partner, Hamburg
,
U. Budde
1   Labor Keeser, Arndt & Partner, Hamburg
› Author Affiliations
Further Information

Publication History

Publication Date:
27 June 2018 (online)

Also available at
    Permissions and Reprints

Zusammenfassung

Die rasante Entwicklung in der Aufklärung angeborener Gerinnungsdefekte, nicht zuletzt durch den Einsatz der molekulargenetischen Diagnostik, hat die Erfolgsrate bei der Ursachenklärung von Thrombosen in den letzten fünf Jahren signifikant erhöht. Die Prävalenz der Thrombophilie wird mit 1 :2500-5000 angegeben und ist somit doppelt so hoch wie die klinisch relevanter Störungen, die mit einer Blutungsneigung einhergehen. Die häufigsten Ursachen der hereditären Thrombophilie, die aktivierte Protein-C-Resistenz, Prothrombinvariante G20210A, Antithrombin-, Protein-C- und Protein-S-Mangel bzw. -dysfunktion sowie die Hyper-homocysteinämie werden hinsichtlich ihrer molekulargenetischen Grundlage, ihres Pathomechanismus, analytischen Besonderheiten und möglicher Therapie beschrieben. Die hereditäre Thrombophilie gilt mittlerweile als Multigendefekt, deren Abklärung anzuraten ist, da sich hieraus für weitere Familienmitglieder in der Prophylaxe und der Therapie betroffener Probanden wichtige therapeutische Konsequenzen ergeben.

Schlüsselwörter

Hereditäre Thrombophilie - Thromboseneigung - Hyperkoagulabilität - molekulargenetische Defekte
 

  • Literatur

  • 1 Aiach M, Borgel D, Gaussem P, Emmerich J, Alhenc-Gelas M, Gandrille S. Protein C and protein S deficiency. Semin Hematol 1997; 34: 205-17.
    PubMedGoogle Scholar
  • 2 Arruda V.R, Annichino-Bizzacchi J.M, Goncalves M.S, Costa F.F. Prevalence of the prothrombin gene variant (nt20210A) in venous thrombosis and arterial disease. Thromb Haemost 1997; 78: 1430-3.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 3 Arruda V.R, Siquiera L.H, Chiaparini L.C, Coelho O.R, Mansur A.P, Ramires A, Anniellino Bizzacchi J.M. Prevalence of the prothrombin gene variant 20210 G→A among patients with myocardial infarction. Cardio-vasc Res 1998; 37: 42-5.
    CrossrefPubMedGoogle Scholar
  • 4 Aschka I, Aumann V, Bergmann F, Budde U, Eberl W, Eckhof-Donovan S, Krey S, Nowak-Göttl U, Schobeß R, Sutor A.H, Wendisch J, Schneppenheim R. Prevalence of factor V Leiden in children with thromboembolism. Eur J Pediatr 1996; 155: 1009-14.
    CrossrefPubMedGoogle Scholar
  • 5 Bauersachs R, Kuhl H, Lindhoff-Last E, Ehrly A.M. Thromboserisiko bei oralen Kontrazeptiva: Stellenwert eines Thrombo-philie-Screening. VASA 1996; 25: 209-20.
    PubMedGoogle Scholar
  • 6 Bertina R.M, van der Linde I.K, Engesser L, Muller H.P, Brommer E.J. Hereditary heparin cofactor II deficiency and the risk of development of thrombosis. Thromb Haemost 1987; 57: 196-200.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 7 Bertina R.M, Koeleman B.P, Koster T, Rosendaal F.R, Dirven R.J, de Ronde H, van der Velden P.A, Reitsma P.H. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-7.
    CrossrefPubMedGoogle Scholar
  • 8 Boushey C.J, Beresford S.A.A, Omenn G.S, Motulski A.G. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. JAMA 1995; 274: 1049-57.
    CrossrefPubMedGoogle Scholar
  • 9 Castaman G, Ruggeri M, Burei F, Rodeghiero F. High levels of histidine rich glygo-protein and familial thrombophilia: A new case. Thromb Res 1993; 69: 279-305.
    CrossrefPubMedGoogle Scholar
  • 10 Cattaneo M. Hyperhomocysteinaemia. Vessel 1997; 3: 16-21.
    PubMedGoogle Scholar
  • 11 Dahlbäck B, Carlsson M, Svensson P.J. 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.
    CrossrefPubMedGoogle Scholar
  • 12 De Stefano V, Chiusolo P, Paciaroni K, Casorelli I, Rossi E, Molinari F, Servidei S, Tonali P.A, Leone G. Prothrombin G20210A mutant genotype is a risk factor for cerebrovascular ischemic disease in young patients. Blood 1998; 91: 3562-5.
    PubMedGoogle Scholar
  • 13 de Visser M.C.H, Rosendaal F.R, Bertina R.M. A reduced sensitivity for activated protein C in the absence of factor V Leiden increases the risk of venous thrombosis. Blood 1999; 93: 1271-6.
    CrossrefPubMedGoogle Scholar
  • 14 den Heijer M, Blom H.J, Gerrits W.B.J, Rosendaal F.R, Haak H.L, Wijermans P.W, Bos G.M.J. Is hyperhomocysteinemia a risk factor for recurrent venous thrombosis?. Lancet 1995; 345: 882-5.
    CrossrefPubMedGoogle Scholar
  • 15 Doggen C.J.M, Cats V.M, Bertina R.M, Rosendaal F.R. Interaction of coagulation defects and cardiovascular risk factors: Increased risk of myocardial infarction associated with factor V Leiden or prothrombin 20210A. Circulation 1998; 97: 1037-41.
    CrossrefPubMedGoogle Scholar
  • 16 Egeberg O. Inherited antithrombin deficiency causing thrombophilia. Thromb Diath Haemorrhag 1965; 116: 754-61.
    PubMedGoogle Scholar
  • 17 Ehrenforth S, Ludwig G, Klinge S, Krause M, Scharrer I, Nowak-Göttl U. The prothrombin 2021 OA Allel is frequently coinhe-rited in young carriers of the factor V Arg 506 to Gin mutation with venous thrombophilia. Blood 1998; 91: 2209-10.
    PubMedGoogle Scholar
  • 18 Esmon C.T. The protein C anticoagulant pathway. Arterioscler Thromb Vase Biol 1992; 12: 135-45.
    CrossrefPubMedGoogle Scholar
  • 19 Falcon C.R, Cattaneo M, Panzeri D, Martinelli I, Mannucci P.M. High prevalence of hyperhomocyst(e)inemia in patients with juvenile venous thrombosis. Arterioscler Thromb Vase Biol 1994; 14: 1080-3.
    CrossrefPubMedGoogle Scholar
  • 20 Ferraresi P, Marchetti G, Legnani C, Cavallari E, Castoldi E, Mascoli F, Ardissino D, Palareti G, Bernardi F. The heterozygous 20210 G/A prothrombin genotype is associated with early venous thrombosis in inherited thrombophilias and is not increased in frequency in artery disaese. Arterioscl Thromb Vase Biol 1997; 17: 2418-22.
    PubMedGoogle Scholar
  • 21 Gallimore M.J, Jones D.W, Winter M. Factor XII determinations in the presence and absence of phospholipid antibodies. Thromb Haemost 1998; 79: 87-90.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 22 Gandrille S, Borgel D, Ireland H. et al. Protein S deficiency: a database of mutations. Thromb Haemost 1997; 77: 1201-14.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 23 Griffin J.H, Evatt B, Wideman C, Fernandez J.A. Anticoagulant protein C pathway defective in majoriy of thrombophilie patients. Blood 1993; 82: 1989-93.
    PubMedGoogle Scholar
  • 24 Halbmayer W.M, Mannhalter C, Feichtinger C, Rubi K, Fischer M. The prevalence of factor FXII deficiency in 103 orally anticoagu-lated patients suffering from venous and/or arterial thromboembolism. Thromb Haemost 1992; 68: 285-90.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 25 Halbmayer W.M, Haushofer A, Hermann K.M, Fischer M. The 20210 A allele of the prothrombin gene: a risk factor for juvenile stroke?. Results of a pilot study. Blood Coag Fibrinol 1998; 9: 209-10.
    CrossrefPubMedGoogle Scholar
  • 26 Haverkate F, Samama M. Familial dysfibri-nogenemia and thrombophilia. Thromb Haemost 1995; 73: 151-61.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 27 Hermann et al. The importance of Hyperhomocysteinemia in High Age people. Clin Lab 1997; 43: 1005-9.
    PubMedGoogle Scholar
  • 28 Jones D.W, Gallimore M.J, Harris S.L, Winter M. Antibodies to factor XII associated with lupus anticoagulant. Thromb Haemost 1999; 81: 387-90.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 29 Kluft C, Dooijewaard G, Emeis J.J. Role of the contact system in fibrinolysis. Sem Thromb Haemost 1987; 13: 50-68.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 30 Lane D.A, Bayston T, Olds R.J. et al. Antithrombin mutation database: 2nd (1997) update. Thromb Haemost 1997; 77: 197-211.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 31 Lentz S.R. Mechanism of thrombosis in hyperhomocysteinemia. Current Opinion in Hematology 1998; 5: 343-9.
    CrossrefPubMedGoogle Scholar
  • 32 Makris M, Preston F.E, Beauchamp N.J, Cooper P.C, Daly M.E, Hampton K.K, Bayliss P, Peake I.R, Miller G.J. Co-inheritance of the 20210 A allele of the prothrombin gene increases the risk of thrombosis in subjects with familial thrombophilia. Thromb Haemost 1997; 78: 1426-9.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 33 Malinow M.R. Plasma homocysteine: a risk factor for arterial occlusive diseases. J Nutr 1996; 126: 1238-43.
    CrossrefPubMedGoogle Scholar
  • 34 Martinelli I, Sacchi E, Landi G, Taioli E, Duca F, Mannuci P.M. High risk of cerebral-vein-thrombosis in carriers of a prothrom-bin-gene mutation and in users of oral contraceptives. N Engl J Med 1998; 338: 1793-7.
    CrossrefPubMedGoogle Scholar
  • 35 Martinez J. Quantitative and qualitative disorders of fibrinogen. In: Hoffman R, Benz Jr E.J, Shattil S.J. et al. (eds) Hematology. Basic Principles and Practice. 2nd ed.. New York: Churchill Livingstone;; 1995: 1703-17.
    Google Scholar
  • 36 Mudd S.H, Levy H.L, Skovby F. Disorders of transsulfuration. In: Sriver C.R, Beaudet A.L, Sly W.S, Valle D, Stanbury J.B, Wyngarden J.B, Fredrickson D.S. (eds) The metabolic and molecular bases of inherited disease. New York: McGraw-Hill; 1995: 1279-327.
    Google Scholar
  • 37 Nygaard O, Nordrehaug J.E, Refsum H, Ueland P.M, Farstad M, Vollset S.E. Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med 1997; 337: 230-6.
    CrossrefPubMedGoogle Scholar
  • 38 Öhlin A-K, Marlar R.A. The first mutation identified in the thrombomodulin gene in a 45-year-old man presenting with thromboembolic disease. Blood 1995; 85: 330-6.
    PubMedGoogle Scholar
  • 39 Öhlin A-K, Marlar R.A. Thrombomodulin gene defects in families with thromboembolic disease - a report of four families. Thromb Haemost 1999; 81: 338-44.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 40 Pabinger I, Schneider B. Thrombotic risk in women with hereditary anti thrombin III-, protein C and protein S-deficiency taking oral contraceptive medication. The GTH Study Group on Natuaral Inhibitors. Thromb Haemost 1994; 71: 548-52.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 41 Perry I.J, Refsum H, Morris R.W, Ebrahim S.B, Ueland P.M, Shaper A.G. Prospective study of total serum homocysteine concentration and risk of stroke in middle-aged British men. Lancet 1995; 346: 1395-8.
    CrossrefPubMedGoogle Scholar
  • 42 Peterson J.C, Spencer J.D. Vitamins and progression of atherosclerosis in hyper-homocyst(e)inaemia. Lancet 1998; 351: 263.
    PubMedGoogle Scholar
  • 43 Poort S.R, Rosendaal F.R, Reitsma P.H. et al. A common genetic variation of the 3’-untranslated region of the prothrombin gene is associated with elevated plasma levels and in increase in venous thrombosis. Blood 1996; 88: 3698-703.
    PubMedGoogle Scholar
  • 44 Rees M.W, Rodgers G.M. Hyperhomocysteinemia: association of a metabolic disorder with vascular disease and thrombosis. Thromb Res 1993; 71: 337-59.
    CrossrefPubMedGoogle Scholar
  • 45 Reitsma P.H, Bernardi F, Doig R.G. et al. Protein C deficiency: A database of mutations. 1995 update. Thromb Haemost 1995; 73: 876-89.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 46 Ridker P.M, Hennekens C.H, Miletich J.P. G20210 A mutation in prothrombin gene and risk of myocardial infarction, stroke and venous thrombosis in a large cohort of US men. Circulation 1999; 99: 999-1004.
    CrossrefPubMedGoogle Scholar
  • 47 Rodeghiero F, Castaman G, Ruggieri M, Tusetto A. Thrombosis in subjects with homozygous and heterozygous factor FXII deficiency. Thromb Haemost 1992; 65: 117-21.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 48 Rosendaal F.R, Siscovick D.S, Schwartz S.M, Beverly R.K, Psaty B.M, Longstreth Jr W.T, Raghundathan T.E, Koepsell T.D, Reitsma P.H. Factor V Leiden (resistance to activated protein C) increases the risk of myocardial infarction in young women. Blood 1997; 89: 2817-21.
    PubMedGoogle Scholar
  • 49 Rosendaal F.R, Vos H.L, Poort S.L, Bertina S.M. Prothrombin 20210A variant and age of thrombosis. Thromb Haemost 1998; 79: 444.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 50 Schwender S, Großmann R, Keller F. High prevalence of factor V Leiden mutaion is detected in a north to south axis through Germany. J Lab Med 1997; 21: 347-52.
    PubMedGoogle Scholar
  • 51 Shigekiyo T, Uno Y, Tomonari A, Satoh K, Hondo H, Ueda S, Saito S. Type I congenital plasminogen deficiency is not a risk factor for thrombosis. Thromb Haemost 1992; 62: 189-92.
    PubMedGoogle Scholar
  • 52 Spannagl M, Dick A, Heinemann L.A.J, Assmann A, Schramm W. Significance of genetic thromboembolic risk factors in the general female population. Results of the Bavarian ThromboEmbolic Risk Study (BATERS). Ann Hematol 1998; 76 (Suppl. 01) A16 V39.
    PubMedGoogle Scholar
  • 53 Vandenbroucke J.P, Koster T, Briet E, Reitsma P.H, Bertina R.M, Rosendaal F.R.T. Increased risk of venous thrombosis in oral contraceptive users who are carriers of factor V Leiden mutation. Lancet 1994; 334: 1453-7.
    PubMedGoogle Scholar
  • 54 van der Bom J.G, Bots M.L, Haverkate F, Slagboom P.E, Meijer P, de Jong PTVM, Hofman A, Grobbee D.E, Kluft C. Reduced response to activated protein C is associated with increased risk for cerebrovascular disease. Ann Intern Med 1996; 125: 265-9.
    CrossrefPubMedGoogle Scholar
  • 55 Williamson D, Brown K, Luddington R, Baglin C, Baglin T. Factor V Cambridge: A new mutation (Arg306→Thr) associated with resistance to activated protein C. Blood 1998; 91: 1140-4.
    PubMedGoogle Scholar
  • 56 Zoller B, Svensson P.J, He X, Dahlbäck B. Identification of the same factor V gene mutation in 47 out of 50 thrombosis-prone families with inherited resistance to activated protein C. J Clin Invest 1994; 94: 2521-4.
    CrossrefPubMedGoogle Scholar