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Hamostaseologie 2008; 28(03): 103-109
DOI: 10.1055/s-0037-1617167
Original Article
Schattauer GmbH

Early days of APC resistance and FV Leiden

Erste Erkenntnisse zu APC-Resistenz und Faktor-V-Leiden
B. Dahlbäck
1   Department of Laboratory Medicine, Section of Clinical Chemistry, Lund University, The Wallenberg laboratory, University Hospital Malmö, Sweden
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Publication History

Publication Date:
29 December 2017 (online)

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Summary

Venous thrombosis is a major medical problem annually affecting millions of individuals worldwide. It is a typical multifactorial disease, the pathogenesis involving both environmental and genetic risk factors. A single point mutation in the gene of coagulation factor V (FV), which results in the replacement of Arg506 with a Gln (FV Leiden) is the most common genetic risk factor known to date. The anti - coagulant activated protein C (APC) regulates the activity of FVa by cleaving several sites in FVa, and the Arg506 is one of them. APC resistance, which is the consequence of the FV Arg506Gln mutation, results a lifelong hypercoagulable state that increases the risk of thrombosis. APC resistance was discovered in my laboratory and the first paper was published in 1993. This was the starting point for an avalanche of research in many laboratories and several thousands of articles have been published since on this topic. The medical community amazingly quickly accepted the concept of APC resistance/FV Leiden as a major risk factor for thrombosis and millions of individuals are today tested for this condition. This review is a personal historical annotation about the early days of APC resistance.

Zusammenfassung

Die Venenthrombose ist ein bedeutendes medizinisches Problem. Jährlich sind weltweit Millionen Menschen davon betroffen. An der Pathogenese der multifaktoriellen Erkrankung sind sowohl erworbene als auch genetische Risikofaktoren beteiligt. Eine Punktmutation im Faktor-V-Gen, die zum Austausch von Arg506 durch ein Gln (Faktor-V-Leiden) führt, ist der häufigste bekannte genetische Risikofaktor. Das Antikoagulanz aktiviertes Protein C (APC) reguliert die Aktivität von Faktor Va durch Spaltung an mehreren Stellen u. a. an Arg506. Die APC-Resistenz, die eine Folge der Faktor-V-Arg506Gln-Mutation ist, führt lebenslang zu erhöhter Gerinnbarkeit, was auch das Thromboserisiko steigert. Die APC-Resistenz wurde in meinem Labor entdeckt, die erste Arbeit wurde 1993 publiziert. Es war der Ausgangspunkt für eine Flut wissenschaftlicher Untersuchungen in zahlreichen Labors. Inzwischen sind mehrere Tausend Artikel zu diesem Thema publiziert. Die Ärzteschaft erkannte das Konzept der APC-Resistenz/FV Leiden als wichtigen Risikofaktor für Thrombose erstaunlich schnell an. Millionen Menschen werden untersucht. Dieser Überblick ist eine persönliche historische Abhandlung zu den Anfangs - tagen der APC-Resistenz.

Keywords

Protein C - factor V - factor V Leiden - FV Leiden - thrombophilia - thrombosis - APC resistance

Schlüsselwörter

Protein C - Faktor V - Faktor-V-Leiden - FV-Leiden - Thrombophilie - Thrombose - APC-Resistenz
 

  • References

  • 1 Moll S, Mackman N. Venous thromboembolism: a need for more public awareness and research into mechanisms. Arterioscler Thromb Vasc Biol 2008; 28: 367-369.
    CrossrefPubMedGoogle Scholar
  • 2 Heit JA. The epidemiology of venous thromboembolism in the community. Arterioscler Thromb Vasc Biol 2008; 28: 370-372.
    CrossrefPubMedGoogle Scholar
  • 3 Moll S. A clinical perspective of venous thromboembolism. Arterioscler Thromb Vasc Biol 2008; 28: 373-379.
    CrossrefPubMedGoogle Scholar
  • 4 Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet 1999; 353: 1167-1173.
    CrossrefPubMedGoogle Scholar
  • 5 Dahlback B. Blood coagulation and its regulation by anticoagulant pathways: genetic pathogenesis of bleeding and thrombotic diseases. J Intern Med 2005; 257: 209-223.
    CrossrefPubMedGoogle Scholar
  • 6 Wakefield TW, Myers DD, Henke PK. Mechanisms of venous thrombosis and resolution. Arterioscler Thromb Vasc Biol 2008; 28: 387-391.
    CrossrefPubMedGoogle Scholar
  • 7 Dahlback B, Villoutreix BO. Regulation of blood coagulation by the protein C anticoagulant pathway: novel insights into structure-function relationships and molecular recognition. Arterioscler Thromb Vasc Biol 2005; 25: 1311-1320.
    CrossrefPubMedGoogle Scholar
  • 8 Malm J, Laurell M, Nilsson IM, Dahlback B. Thromboembolic disease – critical evaluation of laboratory investigation. Thromb Haemost 1992; 68: 7-13.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 9 Dahlback 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: 1004-1008.
    CrossrefPubMedGoogle Scholar
  • 10 Hickton CM, Felding P, Ikeda K, Martinsson G, Nilsson IM. A functional assay of protein C in human plasma. Thromb Res 1986; 41: 501-508.
    CrossrefPubMedGoogle Scholar
  • 11 Segers K, Dahlback B, Nicolaes GA. Coagulation factor V and thrombophilia: background and mechanisms. Thromb Haemost 2007; 98: 530-542.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 12 Nicolaes GA, Tans G, Thomassen MC. et al. Peptide bond cleavages and loss of functional activity during inactivation of factor Va and factor VaR506Q by activated protein C. J Biol Chem 1995; 270: 21158-21166.
    CrossrefPubMedGoogle Scholar
  • 13 Rosing J, Hoekema L, Nicolaes GA. et al. Effects of protein S and factor Xa on peptide bond cleavages during inactivation of factor Va and factor VaR506Q by activated protein C. J Biol Chem 1995; 270: 27852-27858.
    CrossrefPubMedGoogle Scholar
  • 14 Cripe LD, Moore KD, Kane WH. Structure of the gene for human coagulation factor V. Biochemistry 1992; 31: 3777-3785.
    CrossrefPubMedGoogle Scholar
  • 15 Dahlback B, Hildebrand B. Inherited resistance to activated protein C is corrected by anticoagulant cofactor activity found to be a property of factor V. Proc Natl Acad Sci USA 1994; 91: 1396-1400.
    CrossrefPubMedGoogle Scholar
  • 16 Shen L, Dahlback B. Factor V and protein S as synergistic cofactors to activated protein C in degradation of factor VIIIa. J Biol Chem 1994; 269: 18735-18738.
    PubMedGoogle Scholar
  • 17 Thorelli E, Kaufman RJ, Dahlback B. The C-terminal region of the factor V B-domain is crucial for the anticoagulant activity of factor V. J Biol Chem 1998; 273: 16140-16145.
    CrossrefPubMedGoogle Scholar
  • 18 Thorelli E, Kaufman RJ, Dahlback B. Cleavage of factor V at Arg 506 by activated protein C and the expression of anticoagulant activity of factor V. Blood 1999; 93: 2552-2558.
    PubMedGoogle Scholar
  • 19 Varadi K, Rosing J, Tans G, Schwarz HP. Influence of factor V and factor Va on APC-induced cleavage of human factor VIII. Thromb Haemost 1995; 73: 730-731.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 20 Svensson PJ, Dahlback B. Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med 1994; 330: 517-522.
    CrossrefPubMedGoogle Scholar
  • 21 Rosen S, Johansson K, Lindberg K, Dahlback B. Multicenter evaluation of a kit for activated protein C resistance on various coagulation instruments using plasmas from healthy individuals. The APC Resistance Study Group. Thromb Haemost 1994; 72: 255-260.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 22 Griffin JH, Evatt B, Wideman C, Fernandez JA. Anticoagulant protein C pathway defective in majority of thrombophilic patients. Blood 1993; 82: 1989-1993.
    PubMedGoogle Scholar
  • 23 Koster T, Rosendaal FR, de Ronde H. et al. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study. Lancet 1993; 342: 1503-1506.
    CrossrefPubMedGoogle Scholar
  • 24 Dahlback B. Human coagluation factor V purification and thrombin-catalyzed activation. J Clin Invest 1980; 66: 583-591.
    CrossrefPubMedGoogle Scholar
  • 25 Zoller B, Dahlback B. Linkage between inherited resistance to activated protein C and factor V gene mutation in venous thrombosis. Lancet 1994; 343: 1536-1538.
    CrossrefPubMedGoogle Scholar
  • 26 Varadi K, Rosing J, Tans G. et al. Factor V enhances the cofactor function of protein S in the APC-mediated inactivation of factor VIII: influence of the factor VR506Q mutation. Thromb Haemost 1996; 76: 208-214.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 27 Bertina RM, Koeleman BP, Koster T. et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-67.
    CrossrefPubMedGoogle Scholar
  • 28 Sun X, Evatt B, Griffin JH. Blood coagulation factor Va abnormality associated with resistance to activated protein C in venous thrombophilia. Blood 1994; 83: 3120-3125.
    PubMedGoogle Scholar
  • 29 Voorberg J, Roelse J, Koopman R. et al. Association of idiopathic venous thromboembolism with single point-mutation at Arg506 of factor V. Lancet 1994; 343: 1535-1536.
    CrossrefPubMedGoogle Scholar
  • 30 Zoller B, Svensson PJ, He X, Dahlback B. Identification of the same factor V gene mutation in 47 out of 50 thrombosis-prone families with in-herited resistance to activated protein C. J Clin Invest 1994; 94: 2521-2524.
    CrossrefPubMedGoogle Scholar
  • 31 Rees DC, Cox M, Clegg JB. World distribution of factor V Leiden. Lancet 1995; 346: 1133-1134.
    CrossrefPubMedGoogle Scholar
  • 32 Zivelin A, Mor-Cohen R, Kovalsky V. et al. Prothrombin 20210G>A is an ancestral prothrombotic mutation that occurred in whites approximately 24 000 years ago. Blood 2006; 107: 4666-4668.
    CrossrefPubMedGoogle Scholar
  • 33 Dahlback B. The discovery of activated protein C resistance. J Thromb Haemost 2003; 1: 3-9.
    CrossrefPubMedGoogle Scholar
  • 34 Emmerich J, Rosendaal FR, Cattaneo M. et al. Combined effect of factor V Leiden and prothrombin 20210A on the risk of venous thromboembolism-- pooled analysis of 8 case-control studies including 2310 cases and 3204 controls. Study Group for Pooled-Analysis in Venous Thromboembolism. Thromb Haemost 2001; 86: 809-816.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 35 Ridker PM, Hennekens CH, Lindpaintner K. et al. Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men. N Engl J Med 1995; 332: 912-917.
    CrossrefPubMedGoogle Scholar
  • 36 Juul K, Tybjaerg-Hansen A, Steffensen R. et al. Factor V Leiden: The Copenhagen City Heart Study and 2 meta-analyses. Blood 2002; 100: 3-10.
    CrossrefPubMedGoogle Scholar
  • 37 Lindqvist PG, Svensson PJ, Marsaal K. et al. Activated protein C resistance (FV:Q506) and pregnancy. Thromb Haemost 1999; 81: 532-537.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 38 Norstrom E, Thorelli E, Dahlback B. Functional characterization of recombinant FV Hong Kong and FV Cambridge. Blood 2002; 100: 524-530.
    CrossrefPubMedGoogle Scholar