Activated Protein C Resistance — A Major Risk Factor for Thrombosis

Clinical Chemistry and Laboratory Medicine

Volumn 35, Issue 7, 1997, Pages 501-516

  Rosén, Steffen B ^a   Sturk, Augueste ^b  

^a Chromogenix AB   (Sweden)

^b LEIDEN UNIVERSITY MEDICAL CENTER   (Netherlands)

Author keywords

[No Author keywords available]

Indexed keywords

ACTIVATED PROTEIN C; ANTITHROMBIN; ARGININE; BLOOD CLOTTING FACTOR 5; GLUTAMINE; ORAL CONTRACEPTIVE AGENT; PROTEIN C; PROTEIN S;

AMINO ACID SUBSTITUTION; ANTICOAGULATION; AUTOSOMAL DOMINANT INHERITANCE; CAUCASIAN; ELECTROCHEMISTRY; HUMAN; PHENOTYPE; PHOTOMETRY; POINT MUTATION; POLYMERASE CHAIN REACTION; PRIORITY JOURNAL; REVIEW; RISK FACTOR; THROMBOEMBOLISM; THROMBOSIS; TURBIDIMETRY;

ANTIPHOSPHOLIPID SYNDROME; BLOOD COAGULATION; CONTRACEPTIVES, ORAL; DRUG RESISTANCE; ENZYME ACTIVATION; FACTOR V; FEMALE; HOMOCYSTINURIA; HUMANS; PHENOTYPE; POINT MUTATION; POLYMERASE CHAIN REACTION; POSTOPERATIVE COMPLICATIONS; PREGNANCY; PROTEIN C; THROMBOEMBOLISM; THROMBOPHLEBITIS; THROMBOSIS; VASCULAR DISEASES;

EID: 0030877119     PISSN: 14346621     EISSN: 14374331     Source Type: Journal    
DOI: 10.1515/cclm.1997.35.7.501     Document Type: Article

References (177)

1. Goldhaber SZ. Epidemiology of pulmonary embolism and deep venous thrombosis. In: Tuddenham EGD, Bloom AL, Forbes CD, Thomas DP, editors. Haemostasis and thrombosis. Edinburgh: Churchill Livingstone, 1993: 1327-33.
2. Malm J, Laurell M, Nilsson IM, Dahlbäck B. Thromboembolic disease-critical evaluation of laboratory investigation. Thromb Haemost 1992: 68: 7-13.
3. Heijboer H, Brandjes D, Biiller HR, Sturk A, ten Gate JW. Deficiencies of coagulation-inhibiting and fibrinolytic proteins in outpatients with deep-vein thrombosis. N Engl J Med 1990: 323: 1512-6.
4. Tabernero MD, Tomas JF, 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.
5. 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 Sei USA 1993: 90: 1004-8.
6. Svensson PJ, Dahlbäck B. Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med 1994: 330: 517-522.
7. Griffin JH, Evatt B, Wideman C, Fernandez JA. Anticoagulant protein C pathway defective in majority of thrombophilic patients. Blood 1993: 82: 189-193.
8. Koster T, Rosendaal F, de Ronde H, Briet E, Vandenbroucke JP, Bertina RM. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden thrombophilia study. Lancet 1993: 342: 1503-6.
9. Halbmayer WM, Haushofer A, Schön 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 Fibrinolysis 1994: 5: 51-57.
10. 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 Natl Acad Sei USA 1994: 91: 1396-400.
11. Bertina RM, Koeleman BPC, Koster T, Rosendaal FR, Dirven RJ, de Ronde H, et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994: 369: 64-67.
12. Voorberg J, Roelse J, Koopman R, Büller H, Berends F, ten Gate JW, et al. Association of idiopathic venous thromboembolism with single point-mutation at Arg506 of factor V. Lancet 1994: 343: 1535-6.
13. Greengard JS, Sun X, Xu X, Fernandez JA, Griffin JH, Evatt B. Activated protein C resistance caused by Arg506 mutation in factor Va. Lancet 1994: 343: 1361-2.
14. Zöller B, Svensson PJ, He X, Dahlbäck B. Identification of the same factor V gene mutation in 47 out of 50 thrombosisprone families with inherited resistance to activated protein C. J Clin Invest 1994: 94: 2521-4.
15. Simioni P, Scarano L, Gavasso S, Sardella C, Girolami B, Scudeller A, et al. Prothrombin fragment 1 + 2 and thrombinantithrombin complex levels in patients with inherited APC resistance due to factor V Leiden mutation. Br J Haematol 1996: 92: 435-441.
16. Zöller B, Holm J, Svensson P, Dahlbäck B. Elevated levels of prothrombin activation fragment 1 + 2 in plasma from patients with heterozygous Arg506 to Gin mutation in the factor V gene (APC-resistance) and/or inherited protein S deficiency. Thromb Haemost 1996: 75: 270-274.
17. Shen L, Dahlbäck B. Factor V and protein S as synergistic cofactors to activated protein C in degradation of factor VIIIa. J Biol Chem 1994: 269: 18735-8.
18. Väradi K, Rosing J, Tans G, Pabinger I, Keil B, Schwarz HP. Factor V enhance the cofactor function of protein S in the APC-mediated inactivation of factor VIII: influence of the factor V R506Q mutation. Thromb Haemost 1996: 76: 208-214.
19. Lu D, Kalafatis M, Mann K, Long G. Comparison of activated protein C/protein S-mediated inactivation of human factor VIII and factor V. Blood 1996: 87: 4708-17.
20. Beauchamp N, Daly ME, Hampton KK, Cooper PC, Preston FE, 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.
21. Rees DC, Cox M, Clegg JB. World distribution of factor V Leiden. Lancet 1995: 346: 1133-4.
22. Soubrier F, Fery I, Verdy E, Rene MN, Varsat B, Visvikis S, et al. The frequency of the factor V gene R506Q mutation varies between regions of France. Nouv Rev Fr Hematol 1995: 37: 175.
23. Arruda VR, Annichino-Bizzacchi JM, Costa FF, Reitsma PH. Factor V Leiden (FVQ506) is common in a Brazilian population. Am J Hematol 1995: 49: 242-243.
24. Holm J, Zöller B, Berntorp E, Erhardt L, Dahlbäck B. Prevalence of factor V gene mutation amongst myocardial infarction patients and healthy controls is higher in Sweden than in other countries. J Inter Med 1996: 239: 221-226.
25. Schroder W, Koessling M, Wulff K, Wehnert M, Herrmann FH. World distribution of factor V Leiden mutation. Lancet 1996: 347: 58-59.
26. Lee DH, Henderson PA, Blajchman MA. Prevalence of factor V Leiden in a Canadian blood donor population. Can Med Assoc J 1996: 155: 285-289.
27. Chaida C, Gialeraki A, Tsoukala C, Mandalaki T. Prevalence of the FV Q506 mutation in the hellenic population. Thromb Haemost 1996: 76: 127.
28. Gou D, Naipai A, Reitsma PH. World distribution of factor V Leiden mutation. Lancet 1996: 347: 59.
29. Dzimiri N, Meyer B. World distribution of factor V Leiden. Lancet 1996: 347: 481-482.
30. Pottinger P, Sigurdsson F. Detection of the factor V Leiden mutation in a nonselected black population. Blood 1996: 87: 2091.
31. Takamiya O, Ishida F, Kodaira H, Kitano K. APC-resistance and Mnl I genotype (Gin 506) of coagulation factor V are rare in Japanese population. Thromb Haemost 1995: 74: 996.
32. de Maat MPM, Kluft C, Jespersen J, Gram J. World distribution of factor V Leiden mutation. Lancet 1996: 347: 58.
33. Ozawa T, Niiya K, Sakuragawa N. Absence of factor V Leiden in the Japanese. Thromb Haemost 1996: 81: 595-596.
34. Chan LC, Bourke C, Lam CK, Liu HW, Brookes S, Jenkins V, et al. Lack of activated protein C resistance in healthy Hong Kong Chinese blood donors-correlation with absence of Arg506 Gin mutation. Thromb Haemost 1996: 75: 523.
35. Arruda VR, von Suben PM, Scares MCP, Menezes R, Annichino-Bizzacchi JM, Costa FF. Very low incidence of Arg506 → Gin mutation in the factor V gene among the Amazonian Indians and the Brazilian black population. Thromb Haemost 1996: 75: 860-861.
36. Ko YL, Hsu TS, Wu SM, Ko YS, Chang CJ, Wang SM, et al. The G1691A mutation of the coagulation factor V gene (factor V Leiden) is rare in Chinese: an analysis of 618 individuals. Hum Genet 1996: 98: 176-177.
37. Sakata T, Kario K, Katayama Y, Matsuyama T, Kato H, Miyata T. Clinical significance of activated protein C resistance as a potential marker for hypercoagulable state. Thromb Res 1996: 82: 235-244.
38. Fisher M, Fernandez JA, Ameriso SF, Xie D, Gruber A, Paganini-Hill A, et al. Activated protein C resistance in ischemic stroke not due to factor V arginine506 -' glutamine mutation. Stroke 1996: 27: 1163-6.
39. van der Bom JG, Bots ML, Haverkate F, Slagboom E, Meijer P, de Jong PTVM, et al. Reduced response to activated protein C is associated with increased risk for cerebrovascular disease. Ann Intern Med 1996: 125: 265-269.
40. Dahlbäck B, Hillarp A, Rosen S, Zöller B. Resistance to activated protein C, the FV: Q506 allele, and venous thrombosis. Ann Hematol 1996: 72: 166-176.
41. Rosen 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.
42. Dahlbäck B. Resistance to activated protein C, the Arg506 to Gin mutation in the factor V gene, and venous thrombosis. Thromb Haemost 1995: 73: 739-742.
43. Shizuka R, Kanda T, Amagai H, Kobayashi L. False-positive activated protein C (APC) sensitivity ratio caused by freezing and by contamination of plasma with platelets. Thromb Res 1995: 78: 189-190.
44. Sidelmann J, Gram J, Dyg Pedersen O, Jespersen J. Influence of plasma platelets on activated protein C resistance assay. Thromb Haemost 1995: 74: 993-994.
45. Luddington R, Brown K, Baglin T. Effect of platelet phospholipid exposure on activated protein C resistance: implications for thrombophilia screening. Br J Haematol 1996: 92: 744-746.
46. Camire RM, Kalafatis M, Cushman M, Tracy RP, Mann KG, Tracy PB. The mechanism of inactivation of human platelet factor Va from normal and activated protein C-resistant individuals. J Biol Chem 1995: 270: 20794-800.
47. Rosen S, Andersson, NE, Andersson M, Andras M, Zetterberg U, Hall CM. Modified Coatest® APCTM Resistance assay including V-DEF plasma with a heparin antagonist: analysis of heparin and OAC plasmas and influence of preanalytical variables. Blood Coag Fibrinol 1996: 7: 390, P6.
48. Trossaert M, Conard J, Horellou MH, Samama MM. Influence of storage conditions on activated protein C resistance assay. Thromb Haemost 1995: 73: 163.
49. 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.
50. Mathonnet F, de Mazancourt P, Denninger M-H, Morot M, Benattar N, Giudicelli Y. Role of factor VIII on activated protein C resistance ratio in inflammatory diseases. Br J Haematol 1996: 95: 423-425.
51. Jorquera JI, Montoro JM, Fernandez MA, Aznar JA, Aznar J. Modified test for activated protein C resistance. Lancet 1994: 344: 1162-3.
52. Trossaert M, Conard J, Horellou MH, Samama MM, Ireland H, Bayston TA, et al. Modified APC resistance assay for patients on oral anticoagulants. Lancet 1994: 344: 1709.
53. Tosetto A, Rodeghiero F. Diagnosis of APC resistance in patients on oral anticoagulant therapy. Thromb Haemost 1995: 73: 732-733.
54. Cadroy Y, Sie P, Alhenc-Glas M, Aiach M. Evaluation of APC resistance in the plasma of patients with Q506 mutation of factor V (factor V Leiden) and treated by oral anticoagulants. Thromb Haemost 1995: 73: 734-735.
55. Hintz G, Riess H, Huhn D. Inactivation of accelerin determines resistance to activated protein C. Clin Lab 1995: 41: 113-117.
56. Engel H, Zwang L, van Vliet HHDM, Michiels JJ, Stibbe J, Lindemans J. Phenotyping and genotyping of coagulation factor V Leiden. Thromb Haemost 1996: 75: 267-269.
57. Hall CM, Andersson NE, Andersson M, Andras M, Rosen S, Zetterberg U. Complete discrimination for FV: Q506 in plasma from OAC-patients, heparin patients and non-treated individuals using the Coatest® APCTM Resistance assay after predilution in V-DEF plasma. Blood Coagul Fibrinolysis 1996: 7: 390, P5.
58. Nowak-Gottl U, Kohlhase B, Vielhaber H, Aschka I, Schneppenheim R, Jürgens H. APC resistance in neonates and infants: adjustment of the APTT-based method. Thromb Res 1996: 81: 665-670.
59. Trossaert M, Conard J, Horellou MH, Elalamy I, Samama MM. The modified APC resistance test in the presence of factor V deficient plasma can be used in patients without oral anticoagulant. Thromb Haemost 1996: 75: 521-522.
60. Dahlbäck B, Hillarp A, Rosen S, Zöller B. Resistance to activated protein C, the FV: Q506 allele, and venous thrombosis. Ann Hematol 1996: 72: 166-176.
61. Gouault-Heilmann M, Leroy-Matheron C. Factor V Leidendependent APC resistance: improved sensitivity and specificity of the APC resistance test by plasma dilution in factor Vdepleted plasma. Thromb Res 1996: 82: 281-283.
62. Reuner KH, Litfin F, Patscheke H. Discrimination between normal wildtype and carriers of coagulation factor V Leiden mutation by the activated protein C resistance test in the presence of factor V deficient plasma. Eur J Clin Chem Clin Biochem 1997: 35: 41-45.
63. Svensson PJ, Zöller B, Dahlbäck B. Evaluation of original and modified APC-resistance tests in unselected outpatients with clinically suspected thrombosis and in healthy controls. Thromb Haemost 1997: 77: 332-335.
64. Exner T, Murray B, Chong BH, Chesterman CN. Improved APC-resistance method based on a Russel's Viper Venom clotting test [abstract 839]. Thromb Haemost 1995: 73: 1119.
65. Alhenc-Gelas M, Aillaud MF, Bonvarlet MN, Dupuy G, Juhan-Vague I, Aiach M. Specificity of an assay based on a factor V-depleted plasma in patients carrying the Arg506 Gin mutation. Thromb Haemost 1996: 75: 976-977.
66. Le DT, Griffin JH, Greengard JS, Mujumdar V, Rapaport SI. Use of a generally applicable tissue factor-dependent factor V assay to detect activated protein C-resistant factor Va in patients receiving warfarin and in patients with a lupus anticoagulant. Blood 1995: 85: 1704-11.
67. Hoagland LE, Triple DA, Peng F, Barna L. APC-resistance as measured by a Textarin time assay: comparison to the APTT-based method. Thromb Res 1996: 83: 363-373.
68. Varadi K, Moritz B, Lang H, Bauer K, Preston E, Peake I, et al. A chromogenic assay for activated protein C resistance. Br J Haematol 1995: 90: 884-891.
69. Rosen S, Lindberg K, Andersson N-E. A new chromogenic APC resistance assay with high discrimination between absence and presence of the factor V mutation G1691 → A [abstract 1778]. Thromb Haemost 1995: 73: 1364.
70. Nicolaes GAP, Christella M, Thomassen LDG, van Oerle R, Hamulyak K, Hemker HC, et al. A prothrombinase-based assay for detection of resistance to activated protein C. Thromb Haemost 1996: 76: 404-410.
71. de Stefane V, Paciaroni K, Mastrangelo S, Rutella S, Bizzi B, Leone G. Instrument effect on the activated protein C resistance plasma assay performed by a commercial kit. Thromb Haemost 1996: 75: 752-756.
72. Liu XY, Nelson D, Grant C, Morthland V, Goodnight SH, Press RD. Molecular detection of a common mutation in coagulation factor V causing thrombosis via hereditary resistance to activated protein C. Diagn Mol Pathol 1995: 4: 191-197.
73. Voelkerding KV, Wu L, Williams EC, Hoffman SM, Sabatini LM, Borcherding WR, et al. Factor V R506Q gene mutation analysis by PCR-RFLP. Am J Clin Pathol 1996: 106: 100-106.
74. Beauchamp NJ, Daly ME, Cooper PC, Preston FE, Peake R. Rapid two-stage PCR for detecting factor V G1691A mutation. Lancet 1994: 344: 694-695.
75. Kirschbaum NE, Foster PA. The polymerase chain reaction with sequence of specific primers for the detection of the factor V mutation associated with activated protein C resistance. Thromb Haemost 1995: 74: 874-878.
76. Bellissimo DB, Kirschbaum NE, Foster PA. Improved method for factor V Leiden typing by PCR-SSP. Thromb Haemost 1996: 75: 520.
77. Blasczyk R, Ritter M, Thiede C, Wehling J, Hintz G, Neubauer A, et al. Simple and rapid detection of factor V Leiden by allele-specific PCR amplification. Thromb Haemost 1996: 75: 757-759.
78. Rabes JP, Trossaert M, Conard J, Samama MM, Giraudet P, Boileau C. Single point mutation at Arg506 of factor V associated with APC resistance and venous thromboembolism: improved detection by PCR-mediated site-directed mutagenesis. Thromb Haemost 1995: 74: 1379-80.
79. Guillerm C, Lellouche F, Darnige L, Schandelong A, Geoffry F, Dorval I. Rapid detection of the G1691A mutation of coagulation factor V by PCR-mediated site-directed mutagenesis. Clin Chem 1996: 42: 329.
80. Gandrille S, Alhenc-Gelas M, Aiach M. A rapid screening method for the factor V Arg506 -' Gin mutation. Blood Coagul Fibrinolysis 1995: 6: 245-248.
81. Benson J, Phillips D, Holloway B, Evatt B, Hooper C. Oligonucleotide ligation assay for detection of the factor V mutation (Arg506 -' Gin) causing protein C resistance. Thromb Res 1996: 83: 87-96.
82. Zotz RB, Maruhn-Debowski, Scharf RE. Mutation in the gene coding for coagulation factor V and resistance to activated protein C: detection of the genetic mutation by oligonucleotide ligation assay using a semi-automated system. Thromb Haemost 1996: 76: 53-55.
83. von de Locht LTF, Kuypers AWHM, Verbruggen BW, Linssen PCM, Noväkova IRO, Mensink EJBM. Semi-automated detection of the factor V mutation by allele specific amplification and capillary electrophoresis. Thromb Haemost 1995: 74: 1276-9.
84. Peng F, Triple D, Barna L. Direct PCR, of leukocytes treated with microwave irradiation to detect Factor V Leiden mutation. Thromb Res 1996: 82: 193-197.
85. Reitsma PH, van der Velden PA, Vogels E, van Strijp D, Tacken N, Adriaansen H, et al. Use of the direct RNA amplification technique NASBA to detect factor V Leiden, a point mutation associated with APC resistance. Blood Coagul Fibrinolysis 1996: 7: 659-663.
86. Greengard JS, Eichinger S, Griffin J, Bauer K. Variability of thrombosis among homozygous siblings with resistance to activated protein C due to an Arg → Gin mutation in the gene for factor V. N Engl J Med 1994: 33: 1559-62.
87. Samama MM, Simon D, Horellou MH, Trossaert M, Elalamy I, Conard J. Diagnosis and clinical characteristics of inherited activated protein C resistance. Haemostasis 1996: 26: 315-330.
88. Lane DA, Mannucci PM, Bauer KA, Bertina RM, Bochkov NP, Boulyjenkov V, et al. Inherited Thrombophilia*: part 1. Thromb Haemost 1996: 76: 651-662.
89. Munkvad S, Jorgensen M. Resistance to activated protein C: a common anticoagulant deficiency in patients with venous leg ulceration. Br J Dermatol 1996: 134: 296-298.
90. Ridker PM, Miletich J, Stampfer MJ, Goldhaber SZ, Lindpaintner K, Hennekens CH. Factor V Leiden and risks of recurrent idiopathic venous thromboembolism. Circulation 1995: 92: 2800-2.
91. Rintelen C, Pabinger I, Knobl P, Lechner K, Mannhalter C. Probability of recurrence of thrombosis in patients with and without factor V Leiden. Thromb Haemost 1996: 75: 229-232.
92. Simioni P, Prandoni P, Lensing A, Scudeller A, Sardella C, Prins M, et al. The risk of recurrent venous thromboembolism in patients with an Arg506 → Gin mutation in the gene for factor V (factor V Leiden). N Engl J Med 1997: 336: 399-403.
93. Desmarais S, de Moerloose P, Reber G, Minazio P, Ferner A, Bounameaux H. Resistance to activated protein C in an unselected population of patients with pulmonary embolism. Lancet 1996: 347: 1374-5.
94. Manten B, Westendorp RGJ, Koster T, Reitsma P, Rosendaal FR. Risk factor profiles in patients with different clinical manifestations of venous thromboembolism: a focus on the factor V Leiden mutation. Thromb Haemost 1996: 76: 510-513.
95. Martinelli I, Cattaneo M, Panzeri D, Mannucci PM. Low prevalence of factor V: Q506 in 41 patients with isolated pulmonary embolism. Thromb Haemost 1997: 77: 440-443.
96. Zöller B, Berntsdotter 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 1995: 85: 3518-23.
97. Zöller B, He X, Dahlbäck B. Homozygous APC-resistance combined with inherited type 1 protein S deficiency in a young boy with severe thrombotic disease. Thromb Haemost 1995: 73: 743-745.
98. Koeleman BPC, van Rump D, Hamulyak K, Reitsma PH, Bertina RM. Factor V Leiden: an additional risk factor for thrombosis in protein S deficient families? Thromb Haemost 1995: 74: 580-583.
99. Beauchamp N, Daly M, Cooper P, Makris M, Preston E, Peake I. Molecular basis of protein S deficiency in three families also showing independent inheritance of factor V Leiden. Blood 1996: 88: 1700-7.
100. Koeleman BPC, Reitsma PH, Allaart CF, Bertina RM. Activated protein C resistance as an additional risk factor for thrombosis in protein C-deficient families. Blood 1994: 84: 1031-5.
101. Gandrille S, Greengard JS, Alhenc-Gelas M, Juhan-Vague I, Abgrall JF, Jude B, et al. The French network on the behalf of INSERM. Incidence of activated protein C resistance caused by the Arg506 Gin mutation in factor V in 113 unrelated symptomatic protein C-deficient patients. Blood 1995: 86: 219-224.
102. Hallam PJ, Millar DS, Krawzczak M, Kakkar W, Cooper DN. Population differences in the frequency of the factor V Leiden variant among people with clinically symptomatic protein C deficiency. J Med Genet 1995: 32: 543-545.
103. van Boven HH, Reitsma PH, Rosendaal FR, Bayston TA, Chowdhury V, Bauer KA, et al. Factor V Leiden (FV R506Q) in families with inherited antithrombin deficiency. Thromb Haemost 1996: 75: 417-421.
104. Bernardi F, Legnani C, Micheletti F, Lunghi B, Ferraresi P, Palareti G, et al. A heparin cofactor II mutation (HCII Rimini) combined with factor V Leiden or type I protein C deficiency in two unrelated thrombophilic subjects. Thromb Haemost 1996: 76: 505-509.
105. Züger M, Biasiutti FD, Furlan M, Mannhalter C, Lämmle B. Plasminogen deficiency: an additional risk factor for thrombosis in a family with factor V R506Q mutation? Thromb Haemost 1996: 76: 475-476.
106. Poort SR, Rosendaal F, Reitsma PH, Bertina RM. 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.
107. Montalescot G. Homocysteine: the new player in the field of coronary risk. Heart 1996: 76: 101-102.
108. Falcon CR, Cattaneo M, Panzeri D, Martinelli I, Mannucci PM. High prevalence of hyperhomocyst(e)inemia in patients with juvenile venous thrombosis. Arterioscler Thromb 1994: 14: 1080-3.
109. den Heijer M, Blom HJ, Gerrits WBJ. Is hyperhomocysteinaemia a risk factor for recurrent venous thrombosis? Lancet 1995: 345: 882-885.
110. den Heijer M, Koster T, Blom H, Bos G, Briet E, Reitsma P, et al. Hyperhomocysteinemia as a risk factor for deep-vein thrombosis. N Engl J Med 1996: 334: 759-762.
111. Mandel H, Brenner B, Berant M, Rosenberg N, Lanir N, Jakobs C, et al. Coexistence of hereditary homocystinuria and Factor V Leiden-effect on thrombosis. N Engl J Med 1996: 334: 763-768.
112. Peng F, Triplett D, Barna L, Morrical D. Pulmonary embolism and premature labor in a patient with both factor V Leiden mutation and methylenetetrahydrofolate reductase gene C677T mutation. Thromb Res 1996: 83: 243-251.
113. D'Angelo A, Fermo I, D'Angelo SV. Thrombophilia, homocystinuria, and mutation of the factor V gene. New Engl J Med 1996: 335: 289.
114. Quere I, Lamarti H, Chadefaux-Vekemans B. Thrombophilia, homocystinuria, and mutation of the factor V gene. New Engl J Med 1996: 335: 289.
115. Mandel H, Brenner B, Berant M. Thrombophilia, homocystinuria, and mutation of the factor V gene. New Engl. J Med 1996: 335: 290.
116. Department of Health, Welsh Office, Scottish Home and Health, Department of Health and Social Services, Northern Ireland. Confidential enquiries into maternal death in the United Kingdom 1985-87. HMSO, London, 1991.
117. Sipes SL, Weiner CP. Venous thromboembolic disease in pregnancy. Semin Perinatol 1990: 14: 103-118.
118. Bokarewa MI, Bremme K, Blombäck M. Arg506 → Gin mutation in factor V and risk of thrombosis during pregnancy. Br J Haematol 1996: 92: 473-478.
119. 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 1995: 173: 210-213.
120. Grisaru D, Fait G, Eldor A. Activated protein C resistance and pregnancy complications. Am J Obstet Gynecol 1996: 174: 801-802.
121. Hirsch DR, Mikkola KM, Marks PW, Fox EA, Dorfman DM, Ewenstein BM, et al. Pulmonary embolism and deep venous thrombosis during pregnancy or oral contraceptive use: prevalence of factor V Leiden. Am Heart J 1996: 131: 1145-8.
122. Rai R, Regan L, Hadley E, Dave M, Cohen H. Second-trimester pregnancy loss is associated with activated protein C resistance. Br J Haematol 1996: 92: 489-490.
123. de Stefane V, Mastrangelo S, Paciaroni K, Ireland I, Lane DA, Scirpa P, et al. Thrombotic risk during pregnancy and puerperium in women with APC-resistance-effective subcutaneous heparin prophylaxis in a pregnant patient. Thromb Haemost 1995: 74: 793-794.
124. dimming AM, Tait RC, Fildes S, Yoong A, Keeney S, Hay CRM. Development of resistance to activated protein C during pregnancy. Br J Haematol 1995: 90: 725-727.
125. Mathonnet F, de Mazancourt P, Bastenaire B, Morot M, Benattar N, Beufe S, et al. Activated protein C sensitivity ratio in pregnant women at delivery. Br J Haematol 1996: 92: 244-246.
126. Henkens CMA, Bom VJJ, van der Meer J. Lowered APCsensitivity ratio related to increased factor VHI-clotting activity. Thromb Haemost 1995: 74: 1198-9.
127. dimming AM, Campbell R, Fildes S, Hay CRM. Diagnosis of APC resistance during pregnancy. Br J Haematol 1996: 92: 1026-9.
128. Vandenbroucke JP, Koster T, Briet 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: 1453-7.
129. Bloemenkamp KWM, Rosendaal FR, Heimerhorst FM, Büller HR, Vandenbroucke JP. Enhancement by factor V Leiden mutation of risk of deep-vein thrombosis associated with oral contraceptives containing a third-generation progestagen. Lancet 1995: 346: 1593-6.
130. Rosendaal FR, Koster T, Vandenbroucke JP, Reitsma PH. High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance). Blood 1995: 85: 1504-8.
131. Pasi KJ, Perry DJ, Lee CA. Thromboembolism and the combined oral contraceptive pill. Lancet 1995: 345: 1437.
132. Bridey F, Wolff M, Laissy JP, Morin V, Lefebvre M, de Prost D. Fatal cerebral venous sinus thrombosis associated with the factor V Leiden mutation and the use of oral contraceptive. Thromb Haemost 1995: 74: 1382.
133. Olivieri O, Friso S, Manzato F, Guella A, Bernardi F, Lunghi B, et al. Resistance to activated protein C in healthy women taking oral contraceptives. Br J Haematol 1995: 91: 465-470. 134.
134. Solymoss S. Factor V. Leiden: who should be tested? Can Med Assoc J 1996: 155: 296-298.
135. Szucs T, Osterkorn D, Schramm W. Gesundheitsökonomische Evaluation des Screenings of APC-Resistenz (Mutation Leiden) bei Neuanwenderinnen von Ovulationshemmern. Med Klin 1996: 91: 317-319.
136. Rosendaal FR. Oral contraceptives and screening for factor V Leiden. Thromb Haemost 1996: 75: 525.
137. Toulon P, Gris JC, Le Auerrec A, Marnet L. Acquired activated protein C (APC) resistance in women taking oral contraceptives [abstract 260]. Blood 1994: 84 Suppl 1: 68a.
138. österud B, Robertsen R, äsvang GB, Thijssen F. Resistance to activated protein C is reduced in women using oral contraceptives. Blood Coagul Fibrinolysis 1994: 5: 853-854.
139. Henkens CMA, Bom VJJ, Seinen AOJ, van der Meer J. Sensitivity to activated protein C: influence of oral contraceptives and sex. Thromb Haemost 1995: 73: 402-404.
140. Olivieri O, Friso S, Manzato F, Guella A, Bernardu F, Lunghi B, et al. Resistance to activated protein C in healthy women taking oral contraceptives. Br J Haemstol 1995: 91: 465-470.
141. Gris JC, Malassen J, Fabbro-Peray P, Brun S, Sarlat C, Schved JF, et al. Impact of oral contraceptives and postmenopausal hormonal substitution on the plasma response to activated protein C. Haemostasis 1996: 26 Suppl 3: A 465.
142. Daly E, Vessey MP, Hawkins MM, Carson JL, Gough P, Marsh S. Risk of venous thromboembolism inducers of hormone replacement therapy. Lancet 1996: 348: 977-980.
143. Jick H, Derby LE, Wald Meyers M, Vasilakis C, Newton KM. Risk of hospital admission for idiopathic venous thromboembolism among users of postmenopausal oestrogens. Lancet 1996: 348: 981-983.
144. Scarabin PY, Alhenc-Gelas M, Plu-Bureau G, Taisne P, Agher R, Aiach M. Activation of blood coagulation and increased fibrinolytic potential induced by oral but not percutaneous estrogen/progesterone replacement therapy in postmenopausal women-a randomised controlled trial. Haemostasis 1996: 26 Suppl 3: A 466.
145. Alarcon-Segovia D, Sanchez-Guerrero J. Primary antiphospholipid syndrome. J Rheumatol 1989: 16: 482-488.
146. Dizon-Townson D, Hutchison C, Silver R, Branch DW, Ward K. The factor V Leiden mutation which predisposes to thrombosis is not common in patients with antiphospholipid syndrome. Thromb Haemost 1995: 74: 1029-31.
147. Biousse V, Piette JC, Frances C, Bletry O, Papo T, Toumier-Lasserve E, et al. Primary antiphospholipid syndrome is not associated with activated protein C resistance caused by factor V Arg 506 Gin mutation. J Rheumatol 1995: 22: 1215.
148. Ruiz-Argüelles GJ, Garces-Eisele J, Alarcon-Segovia D, Ruiz-Argüelles A. Activated protein C resistance phenotype and genotype in patients with primary antiphospholipid syndrome. Blood Coagul Fibrinolysis 1996: 7: 344-348.
149. Matsuda J, Gohchi K, Tsukamoto M, Gotoh M, Saitoh N, Kawasugi K. Resistance to activated protein C in systemic Lupus erythematosus patients with antiphospholipid antibodies. Eur J Haematol 1994: 53: 188-189.
150. Ehrenforth S, Radtke KP, Scharrer I. Acquired activated protein C-resistance in patients with Lupus anticoagulants. Thromb Haemost 1995: 74: 797-798.
151. Halbmayer WM, Haushofer A, Schön R, Fischer M. Influence of Lupus anticoagulant on a commercially available kit for APC-resistance. Thromb Haemost 1994: 72: 645-646.
152. Gschwandtner ME, Lechner K, Pabinger I. Erroneously low APC ratio in patients with Lupus anticoagulant. Ann Haematol 1995: 70: 169-170.
153. Matsuda J, Gotoh M, Gohchi K, Kawasugi K, Tsukamoto M, Saitoh N. Resistance to activated protein C activity of an antiβ2-glycoprotein I antibody in the presence of β2-glycoprotein I. Br J Haematol 1995: 90: 204-206.
154. Cortese-Hassett A, Bontempo F, Faruki H, Rairie J, Conte C, Medsger T, et al. Activated protein C resistance (APCr) and factor V Leiden in patients with SLE [abstract 805]. Blood 1995: 86 Suppl 1: 204a.
155. Pötzsch B, Kawamura H, Preissner KT, Schmidt M, Seelig C, Müller-Berghaus G. Acquired protein C dysfunction but not decreased activity of thrombomodulin as a possible marker of thrombophilia in patients with Lupus anticoagulant. J Lab Clin Med 1995: 125: 56-65.
156. Gschwandtner ME, Eichinger S, Hütter D, Korninger L, Lechner K, Panzer S, et al. Lupus anticoagulant and thromboembolism: evaluation of fibrinogen, natural inhibitors and molecular markers of thrombosis. Blood Coagul Fibrinolysis 1996: 7: 325-330.
157. Hawkins DW. Global economic perspectives on the use of low molecular weight heparin. Clin Appl Thrombosis/Hemostasis 1996: 2 Suppl 1: 840-843.
158. Bergquist D, Lindgren B, Mätzsch T. Comparison of the cost of preventing postoperative deep vein thrombosis with either unfractionated or low molecular weight heparin. Br J Surgery 1996: 83: 1548-52.
159. Prandoni P, Goldhaber SZ, Piccioli A, Girolami A. Prevention of venous thromboembolism in major orthopedic surgery. Clin Appl Thrombosis/Hemostasis 1996: 2 Suppl 1: 8153-7.
160. Bergqvist D, Benoni G, Björgell O, Fredin H, Hedlundh U, Nicolas S, et al. Low-molecular-weight heparin (Enoxaparin) as prophylaxis against venous thromboembolism after total hip replacement. New Engl J Med 1996: 335: 696-700.
161. Dahl OE, Andreassen G, Aspelin T, Müller C, Mathiesen P, Nyhus S, et al. Prolonged thromboprophylaxis following hip replacement surgery-results of a double-blind, prospective, randomised, placebo-controlled study with Dalteparin (Fragmin ®). Thromb Haemost 1997: 77: 26-31.
162. Emmerich J, Poirier O, Evans A, Marques-Vidal P, Arveiler D, Luc G, et al. Myocardial infarction, Arg 506 to Gin factor V mutation, and activated protein C resistance. Lancet 1995: 345: 321.
163. Ridker PM, Hennekens CH, Lindpaintner K, Stampfer MJ, Eisenberg PR, Miletich JP. 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.
164. Kontula K, Ylikorkala A, Miettinen H, Vuorio A, Kauppinen-Mäkelin R, Hämäläinen L, et al. Arg 506 Gin factor V mutation (factor V Leiden) in patients with ischaemic cerebrovascular disease and survivors of myocardial infarction. Thromb Haemost 1995: 73: 558-560.
165. van Bockxmeer FM, Baker RI, Taylor RR. Premature ischaemic heart disease and the gene for coagulation factor V. Nature Med 1995: 1: 184.
166. Hohn J, Zöller B, Berntorp E, Erhardt L, Dahlbäck B. Prevalence of factor V gene mutation amongst myocardial infarction patients and healthy controls is higher in Sweden than in other countries. J Inter Med 1996: 239: 221-226.
167. Ardissino D, Peyvandi F, Merlini PA, Colombi E, Mannucci PM. Factor V (Arg560-Gin) mutation in young survivors of myocardial infarction. Thromb Haemost 1996: 75: 701-.
168. Simioni P, de Ronde H, Prandoni P, Daladini M, Bertina RM, Girolami A. Ischemic stroke in young patients with activated protein C resistance. A report of three cases belonging to three different kindreds. Stroke 1995: 26: 885-890.
169. Albucher JF, Guiraud-Chaumeil B, Chollet F, Cadroy Y, Sie P. Frequency of resistance to activated protein C due to factor V mutation in young patients with ischemic stroke. Stroke 1996: 27: 766.
170. Landi G, Cella E, Martinelli I, Tagliabue L, Mannucci PM, Zerbi D. Arg 506 Gin factor V mutation and cerebral ischemia in the young. Stroke 1996: 27: 1697-8.
171. Ganesan V, Kelsey H, Cookson J, Osborn A, Kirkham FJ. Activated protein C resistance in childhood stroke. Lancet 1996: 347: 260.
172. Nowak-Göttl U, Koch HG, Aschka I, Kohlhase B, Vielhaber H, Kuriemann G, et al. Resistance to activated protein C (APCR) in children with venous or arterial thromboembolism. Br J Haematol 1996: 92: 992-998.
173. Ouriel K, Green RM, de Weese JA, Cimino C. Activated protein C resistance: prevalence and implications in peripheral vascular disease. J Vase Res 1996: 23: 46-52.
174. Lindblad B, Svensson PJ, Dahlbäck B. Arterial and venous thromboembolism with fatal outcome and resistance to activated protein C. Lancet 1994: 343: 917.
175. Pedersen OD, Gram J, Jespersen J. Plasma resistance to activated protein C regulates the activation of coagulation induced by thrombolysis in patients with ischaemic heart disease. Heart 1997: 77: 122-127.
176. Mari D, Mannucci PM, Duca F, Bertolini S, Frenceschi C. Mutant factor V (Arg506Gln) in healthy centenarians. Lancet 1996: 347: 1044.
177. Eschwege V, Robert A. Strikes in French public transport and resistance to activated protein C. Lancet 1996: 347: 206.