Thromb Haemost 1995; 74(01): 139-148
Schattauer GmbH Stuttgart
New Molecular Insights into the Genetics of Thrombophilia. Resistance to Activated
Protein C Caused by Arg506 to Gin Mutation in Factor V as a Pathogenic Risk Factor for Venous Thrombosis
Björn Dahlbäck
Department of Clinical Chemistry and Coagulation Research, University of Lund, Sweden
› Institutsangaben
References
1
Goldhaber SZ.
TEpidemiology of pulmonary embolism and deep vein thrombosis. In:
Bloom AL,
Forbes CD,
Thomas DP,
Tuddenhamn EG D.
eds.
Haemostasis and Thrombosis. 3rd. ed. Churchill Livinstone: 1994: 1327-1333 2
Thomas DP.
TPathogenesis of venous thrombosis. In:
Bloom AL,
Forbes CD,
Thomas DP,
Tuddenham EG D.
eds.
Haemostasis and Thrombosis. 3rd. ed. Churchill Livingstone: 1994: 1335-1347 3
Allaart CF,
Briët E.
Familial venous thrombophilia. In:
Bloom AL,
Forbes CD,
Thomas DP,
Tuddenham EG D.
eds.
Haemostasis and Thrombosis. 3rd. ed. Churchill Livingstone: 1994: 1349-1360 4
Dahlbä ck,
Malm J,
Laurell M,
Nilsson IM,
Dahlbäck B.
Thromboembolic disease -critical evaluation of laboratory investigation. Thromb Haemost
1992; 68: 7-13 5
Heijboer H,
Brandjes D,
Büller HR,
Sturk A,
ten Cate JW.
Deficiencies of coagulation-inhibiting and fibrinolytic proteins in outpatients with
deep-vein thrombosis. N Engl J Med 1990; 323: 1512-1516 6
Miletich JP,
Prescott SM,
White R,
Majerus PW,
Bovill EG.
Inherited predisposion to thrombosis. Cell 1993; 72: 477-480 7
Tabemero MD,
Tomas IF,
Alberca I,
Orfao A,
Borrasca AL,
Vicente V.
Incidence and clinical characteristics of hereditary disorders associated with venous
thrombosis. Am J Hematol 1991; 36: 249-254 8
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: 1004-1008 9
Bertina RM,
Koeleman BP C,
Koster T,
Rosendaal FR,
Dirven RH,
de Reside H,
vanderVelden PA,
Reitsma PH.
Mutation in blood coagulation factor V associated with resistance to activated protein
C. Nature 1994; 369: 64-67 10
Greengard JS,
Sun X,
Xu X,
Fernandez JA,
Griffin JH,
Evatt B.
Activated protein C resistance caused by Arg506Gln mutation in factor Va. Lancet 1994;
343: 1362-1363 11
Zöller B,
Dahlbäck B.
Linkage between inherited resistance to activated protein C and factor V gene mutation
in venous thrombosis. Lancet 1994; 343: 1536-1538 12
Voorberg J,
Roelse J,
Koopman R,
Büller H,
Berends F,
ten Cate JT,
Mertens K,
vanMourik JA.
Association of idiopathicthromboembolism with single point mutation at Arg506 of factor
V. Lancet 1994; 343: 1535-1536 13
Svensson PJ,
Dahlbäck B.
Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med 1994;
330: 517-521 14
Koster T,
Rosendaal FR,
de Ronde F,
Briët E,
Vandenbroucke JP,
Bertina RM.
Venous thrombosis due to poor response to activated protein C: Leiden thrombophilia
study. Lancet 1993; 342: 1503-1506 15
Davie EW,
Fujikawa K,
Kisiel W.
The coagulation cascade: Initiation, maintainance, and regulation. Biochemistry 1991;
30: 10363-10370 16
Nemerson Y.
Tissue factor and hemostasis. Blood 1988; 71: 1-8 17
Furie B,
Furie BC.
The molecular basis of blood coagulation. Cell 1988; 53: 505-518 18
Kane WH,
Davie EW.
Blood coagulation factors V and VIII: Structural and functional similarities and their
relationship to hemorrhagic and trombotic disorders. Blood 1988; 71: 539-555 19
Jenny RJ,
Tracy PB,
Mann KG.
The physiology and Biochemistry of factor V. In:
Bloom AL,
Forbes CD,
Thomas DP,
Tuddenham EG D.
eds.
Haemostasis and Thrombosis. 3rd. ed. Churchill Livingstone: 1994: 465-476 20
Esmon CT.
Molecular events that control the protein C anticoagulant pathway. Thromb Haemost
1993; 70: 29-35 21
Esmon CT.
Cell mediated events that control blood coagulation and vascular injury. Annu Rev
Cell Biol 1993; 9: 1-26 22
Dahlbäck B.
Protein S and C4b-binding protein: Components involved in the regulation of the protein
C anticoagulant system. Thromb Haemost 1991; 66: 49-61 23
Esmon CT.
The Protein C Anticoagulant Pathway. Arterioscler Thromb 1992; 12: 135-145 24
Dahlbäck B,
Stenflo J.
The protein C anticoagulant system. In:
Stamatoyannopoulos G,
Nienhuis AW,
Majerus PW,
Varmus H.
eds.
The molecular basis of blood diseases. Philadelphia: W:
Saunders B.
1994: 599-628 25
Walker FJ,
Fay PJ.
Regulation of blood coagulation by the protein C system. FASEB J 1992; 6: 2561-2567
26
Shen L,
Dahlbäck B.
Factor V and protein S as synergistic cofactors to activated protein C in degradation
of factor Villa. J Biol Chem 1994; 269: 18735-18738 27
Marlar RA,
Kressin DC,
Madden RM.
Contribution of plasma proteinase inhibitors to the regulation of activated protein
C in plasma. Thromb Haemost 1993; 69: 16-20 28
Fay PJ.
Factor VIII structure and function. Thromb Haemost 1993; 70: 63-67 29
Kalifatis M,
Mann KG.
Role of the membrane in the inactivation of factor Va by activated protein C. J Biol
Chem 1993; 268: 27246-27257 30
Odegaard B,
Mann KG.
Proteolysis of factor Vaby factor Xa and activated protein C. J Biol Chem 1987; 262:
11233-11238 31
Kalafatis M,
Rand MD,
Mann KG.
The mechanism of inactivation ofhuman factor V and human factor Va by activated protein
C. J Biol Chem 1994; 269: 31869-31880 32
Esmon CT.
The roles of protein C and thrombomodulin in the regulation of blood coagulation.
J Biol Chem 1989; 264: 4743-4746 33
Stenflo J.
A new vitamin K-dependent protein. J Biol Chem 1976; 251: 355-363 34
Kisiel W,
Canfield WM,
Ericsson LH,
Davie EW.
`Anticoagulant properties of bovine plasma protein C following activation by thrombin.
J Biol Chem 1977; 16: 5824-5831 35
He X,
Shen L,
Bjartell A,
Malm J,
Lilja H,
Dahlbäck B.
The gene encoding vitamin K-dependent anticoagulant protein C is expressed in human
male reproductive tissues. J Histochem Cytochem. 1995 (in press) 36
Esmon CT,
Owen WG.
Identification of an endothelial cell cofactor for thrombin catalyzed activation of
protein C. Proc Natl Acad Sci USA 1981; 78: 2249-2252 37
Esmon NL,
Owen WG,
Esmon CT.
Isolation of a membrane-bound cofactor forthrombin-catalyzed activation of protein
C. J Biol Chem 1982; 257: 859-864 38
Walker FJ.
Regulation of activated protein Cby a new protein. J Biol Chem 1980; 255: 5521-5524
39
Walker FJ.
Regulation of activated protein C by protein S, the role of phospholipid in factor
Va inactivation. J Biol Chem 1981; 256: 11128-11131 40
Heeb MJ,
Mesters RM,
Tans G,
Rosing J,
Griffin JH.
Binding of protein S to factor Va associated with inhibition of prothrombinase that
is independent of activated protein C. J Biol Chem 1993; 268: 2872-2877 41
Heeb MJ,
Rosing J,
Bakker HM,
Fernandez JA,
Tans G,
Griffin JH.
Protein S binds to and inhibits factor Xa. Proc Nad Acad Sci USA 1994; 91: 2728-2732
42
Hackeng TM,
van’t Veer C,
Meijers JC M,
Bouma BN.
Human protein S inhibits prothrombinase complex activity on endothelial cells and
platelets via direct interactions withfactors Va and Xa. J Biol Chem 1994; 269: 21051-21058
43
Dahlbäck B,
Lundwall Å,
Stenflo J.
Primary structure of bovine vitamin Independent protein S. Proc Natl Acad Sci USA.
44
Discipio RG,
Hermodson MA,
Yates SG,
Davie EW.
A comparison of human prothrombin, factor IX, factor X, and protein S. Biochemisty
1977; 16: 698-706 45
Dahlbäck B,
Stenflo J.
High molecular weight complex in human plasma between vitamin K-dependent protein
S and complement component C4b-binding protein. Proc Natl Acad Sci USA 1981; 78: 2512-2516
46
Dahlbäck B.
Purification of human vitamin K-dependent protein S and its limited proteolysis by
thrombin. Biochem J 1983; 209: 837-846 47
Dahlbäck B.
Purification of human C4b-binding protein and formation of its complex with vitamin
K-dependent protein S. Biochem J 1983; 209: 847-856 48
Dahlbäck B.
Inhibition of protein Ca cofactor function ofhuman and bovine protein S by C4b-binding protein. J Biol Chem
1986; 261: 12022-12027 49
Beitina RM,
van Wijngaarden A,
Reinalda-Poot J,
Poort SR,
Bom VJ.
Determination of plasma protein S - the protein cofactor of activated protein C. Thromb
Haemost 1985; 53: 268-272 50
Comp PC,
Nixon RR,
Cooper MR,
Esmon CT.
Familial protein S deficiency is associated with recurrent thrombosis. J Clin Invest
1984; 74: 2082-2088 51
Suzuki K,
Nishioka J,
Matsuda J,
Maruyama I,
Hashimoto S.
Protein S is essential for the activated protein C-catalyzed inactivation of platelet-associated
factor Va. J Biochem 1984; 96: 455-460 52
Harris KW,
Esmon CT.
Protein S is required for bovine platelets to support activated protein C binding
and activity. J Biol Chem 1985; 260: 2007-2010 53
Stem DM,
Nawroth PP,
Harris KW,
Esmon CT.
Cultured bovine aortic endothelial cells promote activated protein C - protein S-mediated
inactivation of factor Va. J Biol Chem 1986; 261: 713-718 54
Nelsestuen GL,
Kisiel W,
Discipio RG.
Interaction of vitamin K dependent proteins with membranes. Biochemistry 1978; 17:
2134-2138 55
Dahlbäck B,
Wiedmer T,
Sims PJ.
Binding of anticoagulant vitamin K-dependent protein S to platelet-derived microparticles.
Biochemisty 1992; 31: 12769-12777 56
Bakker H,
Tans G,
Janssen-Claessen T,
Thomassen MC L G D,
Hemker HC,
Griffin JH,
Rosing J.
The effect of phospholipids, calcium ions and protein S on rate constants of human
factor Va inactivation by activated human protein C. Eur J Biochem 1992; 208: 171-178
57
Solymoss S,
Tucker MM,
Tracy PB.
Kinetics of inactivation of membrane-bound factor V by activated protein C. J Biol
Chem 1988; 263: 14884-14890 58
Regan LM,
Lamphear BJ,
Walker FJ,
Fay PJ.
Factor IXa protects factor Villa from activated protein C: Factor IXa inhibits activated
protein C- catalyzed cleavage of factor VIIIa at Arg562
. J Biol Chem 1994; 269: 9445-9452 59
Salem HH,
Esmon NL,
Esmon CT,
Majerus PW.
Effects ofthrombomodulin and coagulation factor Va-light chain on protein C activation
in vitro. J Clin Invest 1984; 73: 968-972 60
Gladson CL,
Scharrer I,
Hach V,
Beck KH,
Griffin JH.
The frequency of type I heterozygous protein S and protein C deficiency in 141 unrelated
young patients with venous thrombosis. Thromb Haemost 1988; 59: 18-22 61
Reitsma PH,
Poort SR,
Bemardi F,
Gandrille S,
Long GL,
Sala N,
Cooper DN.
Protein C deficiency: a database of mutations. Thromb Haemost 1993; 69: 77-84 62
Marlar RA,
Neumann A.
Neonatal purpura fulminans due to homozygous protein C or protein S deficiencies.
Semin Thromb Hemost 1990; 16: 299-309 63
Dreyfus M,
Magny JF,
Bridey F,
Schwarz HP,
Planche C,
Dehan M,
Tchemia G.
Treatment of homozygous protein C deficiency and neonatal purpura fulminans with purified
protein C concentrate. N Engl J Med 1991; 325: 1565-1568 64
Bovill EG,
Bauer KA,
Dickermann JD,
Callas P,
West B.
The clinical spectrum of heterozygous protein C deficiency in a large New England
kindred. Blood 1989; 73: 712-717 65
Allaart CF,
Pooit SR,
Rosendaal FR,
Reitsma PH,
Bertina RM,
Briët E.
Increased risk of venous thrombosis in carriers of hereditaiy protein C deficiency
defect. Lancet 1993; 341: 134-138 66
Reitsma PH,
Pooit SR,
Allaait CF,
Briët E,
Bertina RM.
The spectrum of genetic defects in a panel of 40 Dutch families with symptomatic protein
C deficiency type I: Heterogeneity and founder effects. Blood 1991; 78: 890-894 67
Miletich JP,
Sherman L,
Broze Jr GJ.
Absence of thrombosis in subjects with heterozygous protein C deficiency. N Engl J
Med 1987; 317: 991-996 68
Seligsohn U,
Berger A,
Abend A,
Rubin L,
Attias D,
Zivelin A,
Rapaport SI.
Homozygous protein C deficiency manifested by massive thrombosis in the newborn. N
Engl J Med 1984; 310: 559-562 69
Koeleman BP C,
Reitsma PH,
Allaart CF,
Beitina RM.
Activated protein C resistance as an additional risk factor for thrombosis in protein
C-deficient families. Blood 1994; 84: 1031-1035 70
Engesser L,
Broekmans AW,
Briët E,
Brommer EJ P,
Bertina RM.
Hereditaiy protein S deficiency: Clinical manifestations. Ann Intern Med 1987; 106:
677-682 71
Mannucci PM,
Tripodi A,
Bertina RM.
Protein S deficiency associated with “juvenile” arterial and venous thrombosis. Thromb
Haemost 1986; 55: 440-440 72
Allaait CF,
Aronson DC,
Ruys T,
Rosendaal FR,
van Bockel JH,
Bertina RM,
Briët E.
Hereditary protein S deficiency in young adults with arterial occlusive disease. Thromb
Haemost 1990; 64: 206-210 73
Reitsma PH,
Ploos van Amstel HK,
Bertina RM.
Three novel mutations in five unrelated subjects with hereditary protein S deficiency
type I. J Clin Invest 1994; 93: 486-492 74
Gandrille S,
Brogel D,
Eschwege-Gufflet V,
Aillurd MF,
Dreyfus M,
Matheron C,
Gaussem P,
Abgrall JF,
Jude B,
Sié P,
Toulon P,
and
Aiach M.
Identification of 15 different candidate causal point mutations and 3 polymoiphisms
in 19 patients with protein S deficiency using a scanning method for the analysis
of the protein S active gene. Blood 1995; 85: 130-138 75
Schmidel DK,
Nelson RM,
Broxson EH,
Comp PC,
Marlar RA,
Long GL.
A 5.3-kb deletion including exon XIII of the protein S a gene occurs in two protein
S-deficient families. Blood 1991; 77: 551-559 76
Ploos van Amstel HK,
Huisman MV,
Reitsma PH,
ten Cate JW,
Bertina RM.
Partial protein S gene deletion in a family with hereditaiy thrombophilia. Blood 1989;
73: 479-483 77
Bertina RM,
Ploos van Amstel HK,
van Wijngaarden A,
Coenen J,
Leemhuis MP,
Deutz-Terlouw PP,
Van Der Linden IK,
Reitsma PH.
Heerlen polymoiphism of the protein S, an immunologic polymorphism due to dimorphism
of residue 460. Blood 1990; 76: 538-548 78
Comp PC,
Doray D,
Patton D,
Esmon CT.
An abnormal plasma distribution of protein S occurs in functional protein S deficiency.
Blood 1986; 67: 504-508 79
Comp PC,
Esmon CT.
Recurrent thromboembolism in patients with a partial deficiency of protein S. N Engl
J Med 1984; 311: 1525-1528 80
Schwarz HP,
Fischer M,
Hopmeier P,
Batard MA,
Griffin IH.
Plasma protein S deficiency in familial thrombotic disease. Blood 1984; 64: 1297-1300
81
Zöller B,
Garcia de Frutos P,
Dahlbäck B.
Evaluation of the relationship between protein S and C4b-binding protein isofoims
in hereditary protein S deficiency demonstrating type I and type III deficiencies
to be phenotypic variants of the same genotype. Blood. 1994 submitted: 82
Mannucci PM,
Valsecchi C,
Krashmalnicoff A,
Faioni EM,
Tripodi A.
Familial dysfunction of protein S. Thromb Haemost 1989; 62: 763-766 83
Hayashi T,
Nishioka J,
Shigekiyo T,
Saito S,
Suzuki K.
Protein S Tokushima: abnormal molecule with a substitution of Glu for Lys-155 in the
second epidermal growth factor-like domain of protein S. Blood 1994; 83: 683-690 84
Faioni EM,
Franchi F,
Asti D,
Sacchi E,
Bemardi F,
Mannucci PM.
Resi stance to activated protein C in nine thrombophilic families: Interference in
a protein S functional assay. Thromb Haemost 1993; 70: 1067-1071 85
Dahlbäck B.
Thrombophilia. In:
Friedmann T,
Gianelli FG.
eds.
Advances in Genetics. Orlando,FL: Academic Press; 1995. in press 86
Dahlbäck B,
Hildebrand B.
Inherited resistance to activated protein C is corrected by anticoagulant cofactor
activity found to be a property of factor V. Proc Nad Acad Sci USA 1994; 81: 1396-1400
87
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 88
Beauchamp NJ,
Daly ME,
Hampton KK,
Cooper PC,
Preston E,
Peake IR.
High prevalence of a mutation in the factor V gene within the UK population: Relationship
to activated protein C resistance and familial thrombosis. Br J Haematol 1994; 88:
219-222 89
Baker R,
Thom J,
Vanbockxmeer F.
Diagnosis of activated protein C resistance (factor V Leiden). Lancet 1994; 344: 1162-1162
90
Alhenc-Gelas M,
Gandrille S,
Aubry ML,
Emmerich J,
Fiessinger JN,
Aiach M.
Unexplained thrombosis and factor V Leiden mutation. Lancet 1994; 344: 555-556 91
Hellgren M,
Svensson PJ,
Dahlbäck B.
Resistance to activated protein C as a basis for venous thromboembolism associated
with pregnancy and oral contraceptives. Am J Obstet Gynecol. 1994 submitted: 92
Svensson PJ,
Dahlbäck B.
Novel mechanism for thrombosis characterized by poor anticoagulant response to activated
protein C constitutes a major cause of thrombophilia. Thromb Haemost 1993; 69: 999-999
93
Svensson PJ,
Dahlbäck B.
Twenty novel families with thrombophilia and inherited resistance to activated protein
C. Thromb Haemost 1993; 69: 1252 (abstract) 94
Griffin JH,
Evatt B,
Wideman C,
Fernandez JA.
Anticoagulant protein C pathway defective in a majority of thrombophilic patients.
Blood 1993; 82: 1989-1993 95
Halbmayer WM,
Haushofer A,
Schon R,
Fischer M.
The prevalence of poor anticoagulant response to activated protein C (APC resistance)
among patients suffering from stroke or venous thrombosis and among healthy subjects.
Blood Coagul Fibrinol 1994; 5: 51-57 96
Lindblad B,
Svensson PJ,
Dahlback B.
Arterial and venous thromboembolism with fatal outcome in a young man with inherited
resistance to activated protein C. Lancet 1994; 343: 917-917 97
Holm J,
Zöller B,
Svensson PJ,
Bemtorp E,
Erhardt L,
Dahlbäck B.
Myocardial infarction associated with homozygous resistance to activated protein C.
Lancet 1994; 344: 952-953 98
Cushman M,
Bhushan F,
Bovill E,
Tracy R.
Plasma resistance to activated protein C in venous and arterial thrombosis. Thromb
Haemost 1994; 72: 647-647 99
Samani NJ,
Lodwick D,
Martin D,
Kimber P.
Resistance to activated protein C and risk of premature myocardial infarction. Lancet
1994; 344: 1709-1710 100
Zöller B,
Svensson PJ,
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:
2521-2524 101
Dahlbäck B.
Physiological anticoagulation. Inherited resistance to activated protein C and venous
thromboembolism. J Clin Invest 1994; 94: 923-927 102
Zöller B,
Bemtsdotter A,
Garcia de Frutos P,
Dahlbäck B.
Resistance to activated protein C as an additional genetic risk factor in hereditary
deficiency of protein S. Blood. 1994 in press 103
Vandenbroucke JP,
Koster T,
Briët E,
Reitsma PH,
Bertina RM,
Rosendaal FR.
Increased risk of venous thrombosis in oral -contraceptive users who are carriers
of factor V Leiden mutation. Lancet 1994; 344: 1453-1457 104
Majerus PW.
Bad blood by mutation. Nature 1994; 369: 14-15 105
de Ronde H,
Bertina RM.
Laboratory diagnosis of APC-resistance: a critical evaluation of the test and the
development of diagnostic criteria. Thromb Haemost 1994; 72: 880-886 106
Rosén S,
Johansson K,
Lindberg K,
Dahlbäck B.
Multicenter evaluation of a kit for activated protein C resistance on various coagulation
instruments using plasmas from healthy individuals. Thromb Haemost 1994; 72: 255-260
107
Jorquera JI,
Montoro JM,
Fernandez MA,
Aznar JA,
Aznar J.
Modified test for activated protein C resistance. Lancet 1994; 344: 1162-1163 108
Trossaert M,
Conard J,
Horellou MH,
Samama MM,
Ireland H,
Bayston TA,
Lane DA.
Modified APC resistance assay for patients on oral anticoagulants. Lancet 1994; 344:
1709-1709 109
Cripe LD,
Moore KD,
Kane WH.
Structure of the geneforhuman coagulation factor V. Biochemistry 1992; 31: 3777-3785
110
Bauer KA.
Hypercoagulability - a new cofactor in the protein C anticoagulant pathway. N Engl
J Med 1994; 330: 566-567 111
Dahlbäck B.
Bovine coagulation factor V visualized with electron microscopy; ultra structure of
the isolated activated forms and of the activation fragments. J Biol Chem 1986; 261:
9495-9501 112
Dahlbäck B.
Inherited thrombophilia. Resistance to activated protein C as a basis for venous thromboembolism.
Blood 1995; 85: 607-614
