The propensity for both arterial and venous thrombotic disorders involves a genetic predetermination that operates In concert with environmental factors or triggers. Appropriate clinical assessment and therapeutic recommendations for patients with thrombosis requires a thorough knowledge of genetic variables that influence this propensity. This review focuses on the pathophysiology, natural history, and molecular biology of defined thrombophilic risk factors relevant to the care of patients with thrombotic disorders.
2. Karnicki K, Owen WG, Miller RS, et al: Factors contributing to individual propensity for arterial thrombosis. Arterioscler Thromb Vasc Biol22:1495-1499, 2002.
3.
3. Qiao JH, Fishbein MC, et al: The severity of coronary atherosclerosis at sites of plaque rupture with occlusive thrombosis. J Am Coll Cardiol17:1138-1142, 1991.
4.
4. Falk E: Plaque rupture with severe pre-existing stenosis precipitating coronary thrombosis. Characteristics of coronary atherosclerotic plaques underlying fatal occlusive thrombi. Br Heart J50:127-134, 1983.
5.
5. Davies MJ, Thomas A: Thrombosis and acute coronaryartery lesions in sudden cardiac ischemic death. N Engl J Med310:1137-1140, 1984.
6.
6. Kullo IJ, Edwards WD, Schwartz RS: Vulnerable plaque: Pathobiology and clinical implications. Ann Int Med129:1050-1060, 1998.
7.
7. Da Costa A, Isaaz K, Faure E, et al: Clinical characteristics, aetiological factors and long-term prognosis of myocardial infarction with an absolutely normal coronary angiogram; a 3-year follow-up study of 91 patients. Eur Heart J22:1459-1465, 2001.
8.
8. van Boven, Lane DA: Antithrombin and its inherited deficiency states. Sem Hematol34:188-204, 1997.
10. Bayston TA, Lane DA: Antithrombin: Molecular basis of deficiency. Thromb Haemost78:339-343, 1997.
11.
11. Lane DA, Bayston T, Olds RJ, et al: Antithrombin mutation database: 2nd (1997) update. For the Plasma Coagulation Inhibitors Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost77:197-211, 1997.
12.
12. Conlan MG, Folsom AR, Finch A, et al: Antithrombin III: Associations with age, race, sex and cardiovascular disease risk factors. The Atherosclerosis Risk in Communities (ARIC) Study Investigators. Thromb Haemost72:551-556, 1994.
13.
13. Wells PS, Blajchman MA, Henderson P, et al: Prevalence of antithrombin deficiency in healthy blood donors: A cross-sectional study. American J Hematol45:321-324, 1994.
14.
14. Tait RC, Walker ID, Perry DJ, et al: Prevalence of antithrombin deficiency in the healthy population. Br J Haematol87:106-112, 1994.
15.
15. Thaler E, Lechner K: Antithrombin III deficiency and thromboembolism. Clin Haematol10:369-390, 1981.
16.
16. Rosendaal FR, Heijboer H, Briet E, et al: Mortality in hereditary antithrombin-III deficiency-1830 to 1989. Lancet337:260-262, 1991.
17.
17. de Boer AC, van Riel LA, den Ottolander GJ: Measurement of antithrombin III, alpha 2-macroglobulin and alpha 1-antitrypsin in patients with deep venous thrombosis and pulmonary embolism. Thromb Res15:17-25, 1979.
18.
18. Damus PS, Wallace GA: Immunologic measurement of antithrombin III-heparin cofactor and alpha2 macroglobulin in disseminated intravascular coagulation and hepatic failure coagulopathy. Thromb Res6:27-38, 1975.
19.
19. Kauffmann RH, Veltkamp JJ, Van Tilburg NH, et al: Acquired antithrombin III deficiency and thrombosis in the nephrotic syndrome. Am J Med65:607-613, 1978.
20.
20. Weenink GH, Kahle LH, Lamping RJ, et al: Antithrombin III in oral contraceptive users and during normotensive pregnancy. Acta Obstet Gynecol Scand63:57-61, 1984.
21.
21. Buchanan GR, Holtkamp CA: Reduced antithrombin III levels during L-asparaginase therapy. Med Pediatr Oncol8:7-14, 1980.
22.
22. Marciniak E, Gockerman JP: Heparin-induced decrease in circulating antithrombin-III. Lancet2:581-584, 1977.
23.
23. Hirsh J, Warkentin TE, Shaughnessy SG, et al: Heparin and low-molecular-weight heparin: Mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. Chest119:64S-94S, 2001.
24.
24. Esmon NL, Owen WG, Esmon CT: Isolation of a membrane-bound cofactor for thrombin-catalyzed activation of protein C. J Biol Chem257:859-864, 1982.
25.
25. Esmon CT, Fukudome K: Cellular regulation of the protein C pathway. Sem Cell Biol6:259-268, 1995.
26.
26. Bertina RM, Koeleman BP, Koster T, et al: Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature369:64-67, 1994.
27.
27. 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 Chem270:27852-27858, 1995.
28.
28. Griffin JH, Evatt B, Zimmerman TS, et al: Deficiency of protein C in congenital thrombotic disease. J Clin Invest68:1370-1373, 1981.
29.
29. Marciniak E, Wilson HD, Marlar RA: Neonatal purpura fulminans: A genetic disorder related to the absence of protein C in blood. Blood65:15-20, 1985.
30.
30. Seligsohn U, Berger A, Abend M, et al: Homozygous protein C deficiency manifested by massive venous thrombosis in the newborn. N Engl J Med310:559-562, 1984.
31.
31. Tait RC, Walker ID, Reitsma PH, et al: Prevalence of protein C deficiency in the healthy population. Thromb Haemost73:87-93, 1995.
32.
32. Miletich J, Sherman L, Broze G Jr: Absence of thrombosis in subjects with heterozygous protein C deficiency. N Engl J Med317:991-996, 1987.
33.
33. Folsom AR, Aleksic N, Wang L, et al: Protein C, antithrombin, and venous thromboembolism incidence: A prospective population-based study. Arterioscl Thromb Vasc Biol22:1018-1022, 2002.
34.
34. Bovill EG, Bauer KA, Dickerman JD, et al: The clinical spectrum of heterozygous protein C deficiency in a large New England kindred. Blood73:712-717, 1989.
35.
35. Allaart CF, Poort SR, Rosendaal FR, et al: Increased risk of venous thrombosis in carriers of hereditary protein C deficiency defect. Lancet341:134-138, 1993.
36.
36. Reitsma PH, Bernardi F, Doig RG, et al: Protein C deficiency: A database of mutations, 1995 update. On behalf of the Subcommittee on Plasma Coagulation Inhibitors of the Scientific and Standardization Committee of the ISTH. Thromb Haemost173:876-889, 1995.
37.
37. Reitsma PH: Protein C deficiency: Summary of the 1995 database update. Nucleic Acids Res124:157-159, 1996.
38.
38. Koeleman BP, Reitsma PH, Allaart CF, et al: Activated protein C resistance as an additional risk factor for thrombosis in protein C-deficient families. Blood84:1031-1035, 1994.
39.
39. Gandrille S, Greengard JS, Alhenc-Gelas M, et al: Incidence of activated protein C resistance caused by the ARG 506 GLN mutation in factor V in 113 unrelated symptomatic protein C-deficient patients. The French Network on the behalf of INSERM. Blood86:219-224, 1995.
40.
40. Aiach M, Borgel D, Gaussem P. et al: Protein C and protein S deficiencies. Sem Hematol34:205-216, 1997.
41.
41. Tamosiuniene R, Plumhoff EA, Nichols WL, et al: Plasma factor VII activity as a predictor of congenital protein C deficiency among thrombophilia patients receiving oral anticoagulation therapy. Thromb Haemost Aug1999; suppl:550-550, (Abstract #1732).
42.
42. Pescatore P.Horellou HM, Conard J, et al: Problems of oral anticoagulation in an adult with homozygous protein C deficiency and late onset of thrombosis. Thromb Haemost69:311-315, 1993.
43.
43. Miura Y, Ardenghy M, Ramasastry S, et al: Coumadin necrosis of the skin: Report of four patients. Ann Plast Surg37:332-337, 1996.
44.
44. Jillella AP, Lutcher CL: Reinstituting warfarin in patients who develop warfarin skin necrosis. Am J Hematol52:117-119, 1996.
45.
45. Dahlback B: The protein C anticoagulant system: Inherited defects as basis for venous thrombosis. Thromb Res77(1):1-43, 1995.
46.
46. 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 Chem270:27852-27858, 1995.
47.
47. Mitchell CA, Kelemen SM, Salem HH: The anticoagulant properties of a modified form of protein S. Thromb Haemost60:298-304, 1988.
48.
48. van't Veer C, Hackeng TM, Biesbroeck D, et al: Increased prothrombin activation in protein S-deficient plasma under flow conditions on endothelial cell matrix: An independent anticoagulant function of protein S in plasma. Blood85:1815-1821, 1995.
49.
49. Heeb MJ, Mesters RM, Tans G, et al: Binding of protein S to factor Va associated with inhibition of prothrombinase that is independent of activated protein C. J Biol Chem268:2872-2877, 1993.
50.
50. Heeb MJ, Rosing J, Bakker HM, et al: Protein S binds to and inhibits factor Xa. Proc Nat Acad Sci91:2728-2732, 1994.
51.
51. Hackeng TM, van't Veer C, Meijers JC, et al: Human protein S inhibits prothrombinase complex activity on endothelial cells and platelets via direct interactions with factors Va and Xa. J Biol Chem269:21051-21058, 1994.
52.
52. Dahlback B: Protein S and C4b-binding protein: Components involved in the regulation of the protein C anticoagulant system. Thromb Haemost66:49-61, 1991.
53.
53. Liberti G, Bertina RM, Rosendaal FR: Hormonal state rather than age influences cut-off values of protein S: Reevaluation of the thrombotic risk associated with protein S deficiency. Thromb Haemost82(3):1093-1096, 1999.
54.
54. Comp PC, Thurnau GR, Welsh J, et al: Functional and immunologic protein S levels are decreased during pregnancy. Blood68(4):881-885, 1986.
55.
55. Boerger LM, Morris PC, Thurnau GR, et al: Oral contraceptives and gender affect protein S status. Blood69:692-694, 1987.
56.
56. Cushman M, Costantino JP, Bovill EG, et al: Effect of tamoxifen on venous thrombosis risk factors in women without cancer: The Breast Cancer Prevention Trial. Br J Haematol120:109-116, 2003.
57.
57. D'Angelo A, Vigano-D'Angelo S, Esmon CT, et al: Acquired deficiencies of protein S. Protein S activity during oral anticoagulation, in liver disease, and in disseminated intravascular coagulation. J Clin Invest81:1445-1454, 1988.
58.
58. Garcia de Frutos P., Alim RI, Hardig Y, et al: Differential regulation of alpha and beta chains of C4b-binding protein during acute-phase response resulting in stable plasma levels of free anticoagulant protein S. Blood84:815-822, 1994.
59.
59. Ploos van Amstel JK, van der Zanden AL, Bakker E, et al: Two genes homologous with human protein S cDNA are located on chromosome 3. Thromb Haemost58:982-987, 1987.
60.
60. Dykes AC, Walker ID, McMahon AD, et al: A study of Protein S antigen levels in 3788 healthy volunteers: Influence of age, sex and hormone use, and estimate for prevalence of deficiency state. Br J Haematol113:636-641, 2001.
61.
61. Heijboer H, Brandjes DP, Buller HR, et al: Deficiencies of coagulation-inhibiting and fibrinolytic proteins in outpatients with deep-vein thrombosis. N Engl J Med323:1512-1516, 1990.
62.
62. Pabinger I, Brucker S, Kyrle PA, et al: Hereditary deficiency of antithrombin III, protein C and protein S: prevalence in patients with a history of venous thrombosis and criteria for rational patient screening. Blood Coag Fibrinol3:547-553, 1992.
63.
63. Gladson CL, Scharrer I, Hach V, et al: The frequency of type I heterozygous protein S and protein C deficiency in 141 unrelated young patients with venous thrombosis. Thromb Haemost59:18-22, 1988.
64.
64. Pabinger I, Schneider B: Thrombotic risk in hereditary antithrombin III, protein C, or protein S deficiency. A cooperative, retrospective study. Gesellschaft fur Thromboseund Hamostaseforschung (GTH) Study Group on Natural Inhibitors. Arterioscler Thromb Vasc Biol16:742-748, 1996.
65.
65. Pabinger I, Kyrle PA, Heistinger M, et al: The risk of thromboembolism in asymptomatic patients with protein C and protein S deficiency: A prospective cohort study. Thromb Haemost71:441-445, 1994.
66.
66. Zoller B, Berntsdotter A, Garcia de Frutos P, et al: Resistance to activated protein C as an additional genetic risk factor in hereditary deficiency of protein S. Blood85:3518-3523, 1995.
67.
67. Koeleman BP, van Rumpt D, Hamulyak K, et al: Factor V Leiden: An additional risk factor for thrombosis in protein S deficient families?Thromb Haemost74:580-583, 1995.
68.
68. 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 USA90:1004-1008, 1993.
69.
69. De Stefano V, Paciaroni K, Mastrangelo S, et al: Instrument effect on the activated protein C resistance plasma assay performed by a commercial kit. Thromb Haemost75:752-756, 1996.
70.
70. Sweeney JD, Blair AJ, King TC: Comparison of an activated partial thromboplastin time with a Russell viper venom time test in screening for factor V(Leiden) (FVR506Q). Am J Clin Pathol108:74-77, 1997.
71.
71. Akhtar MS, Blair AJ, King TC, et al: Whole blood screening test for factor V Leiden using a Russell viper venom time-based assay. Am J Clin Pathol109:387-391, 1998.
72.
72. Corral J, Iniesta JA, Gonzalez-Conejero R, et al: Detection of factor V Leiden from a drop of blood by PCR-SSCP. Thromb Haemost76:735-737, 1996.
73.
73. Rees DC, Cox M, Clegg JB: World distribution of factor V Leiden. Lancet346:1133-1134, 1995.
74.
74. Larsen TB, Lassen JF, Brandslund I, et al: The Arg5O6Gln mutation (FV Leiden) among a cohort of 4188 unselected Danish newborns. Thromb Res89:211-215, 1998.
75.
75. Ko YL, Hsu TS, Wu 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 Genet98:176-177, 1996.
76.
76. Herrmann FH, Koesling M, Schroder W, et al: Prevalence of factor V Leiden mutation in various populations. Genet Epidemiol14:403-411, 1997.
77.
77. Pepe G, Rickards O, Vanegas OC, et al: Prevalence of factor V Leiden mutation in non-European populations. Thromb Haemost77:329-331, 1997.
78.
78. Kim TW, Kim WK, Lee JH, et al: Low prevalence of activated protein C resistance and coagulation factor V Arg5O6 to Gln mutation among Korean patients with deep vein thrombosis. J Korean Med Sci13:587-590, 1998.
79.
79. Koster T, Rosendaal FR, de Ronde H, et al: Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study. Lancet342:1503-1506, 1993.
80.
80. Griffin JH, Evatt B, Wideman C, et al: Anticoagulant protein C pathway defective in majority of thrombophilic patients. Blood82:1989-1993, 1993.
81.
81. de Visser MC, Rosendaal FR, Bertina RM: A reduced sensitivity for activated protein C in the absence of factor V Leiden increases the risk of venous thrombosis. Blood93:1271-1276, 1999.
82.
82. Rodeghiero F, Tosetto A: Activated protein C resistance and factor V Leiden mutation are independent risk factors for venous thromboembolism. Ann Intern Med130:643-650, 1999.
83.
83. 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 Med332:912-917, 1995.
84.
84. Rosendaal FR, Koster T, Vandenbroucke JP, et al: High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance). Blood85:1504-1508, 1995.
85.
85. Emmerich J, Alhenc-Gelas M, Aillaud MF, et al: Clinical features in 36 patients homozygous for the ARG 506->GLN factor V mutation. Thromb Haemost77:620-623, 1997.
86.
86. Zoller B, Svensson PJ, He X, et al: Identification of the same factor V gene mutation in 47 out of 50 thrombosisprone families with inherited resistance to activated protein C. J Clin Invest94:2521-2524, 1994.
87.
87. Koeleman BP, Reitsma PH, Allaart CF, et al: Activated protein C resistance as an additional risk factor for thrombosis in protein C-deficient families. Blood84:1031-1035, 1994.
88.
88. Koeleman BP, van Rumpt D, Hamulyak K, et al: Factor V Leiden: an additional risk factor for thrombosis in protein S deficient families?Thromb Haemost74:580-583, 1995.
89.
89. De Stefano V, Martinelli I, Mannucci PM, et al: The risk of recurrent deep venous thrombosis among heterozygous carriers of both factor V Leiden and the G20210A prothrombin mutation. N Engl J Med341:801-806, 1999.
90.
90. van Boven HH, Reitsma PH, Rosendaal FR, et al: Factor V Leiden in families with inherited antithrombin deficiency. Thromb Haemost75:417-421, 1996.
91.
91. De Mitrio V, Marino R, Scaraggi FA, et al: Influence of factor VIII/von Willebrand complex on the activated protein C-resistance phenotype and on the risk for venous thromboembolism in heterozygous carriers of the factor V Leiden mutation. Blood Coagul Fibrinolysis10:409-416, 1999.
92.
92. Mandel H, Brenner B, Berant M, et al: Coexistence of hereditary homocystinuria and factor V Leiden-effect on thrombosis. N Engl J Med334:763-768, 1996.
93.
93. Brenner B, Vulfsons SL, Lanir N, et al: Coexistence of familial antiphospholipid syndrome and factor V Leiden: Impact on thrombotic diathesis. Br J Haematol94:166-167, 1996.
94.
94. Simioni P, Scudeller A, Radossi P, et al: “Pseudo homozygous” activated protein C resistance due to double heterozygous factor V defects (factor V Leiden mutation and type I quantitative factor V defect) associated with thrombosis: report of two cases belonging to two unrelated kindreds. Thromb Haemost75:422-426, 1996.
95.
95. Ridker PM, Miletich JP, Stampfer MJ, et al: Factor V Leiden and risks of recurrent idiopathic venous thromboembolism. Circulation92:2800-2802, 1995.
96.
96. Hainaut P, Azerad MA, Lehmann E, et al: Prevalence of activated protein C resistance and analysis of clinical profile in thromboembolic patients. A Belgian prospective study. J Intern Med241:427-433, 1997.
97.
97. Simioni P, Prandoni P, Lensing AW, et al: The risk of recurrent venous thromboembolism in patients with an Arg506- - >Gln mutation in the gene for factor V (factor V Leiden). N Engl J Med336:399-l403, 1997.
98.
98. Simioni P, Prandoni P, Lensing AW, et al: Risk for subsequent venous thromboembolic complications in carriers of the prothrombin or the factor V gene mutation with a first episode of deep-vein thrombosis. Blood96:3329-3333, 2000.
99.
99. Rintelen C, Pabinger I, Knobl P, et al: Probability of recurrence of thrombosis in patients with and without factor V Leiden [see comments]. Thromb Haemost75:229-232, 1996.
100.
100. Eichinger S, Pabinger I, Stumpflen A, et al: The risk of recurrent venous thromboembolism in patients with and without factor V Leiden. Thromb Haemost77:624-628, 1997.
101.
101. Lindmarker P, Schulman S, Sten-Linder M, et al: The risk of recurrent venous thromboembolism in carriers and noncarriers of the G1691A allele in the coagulation factor V gene and the G20210A allele in the prothrombin gene. DURAC Trial Study Group. Duration of Anticoagulation. Thromb Haemost81:684-689, 1999.
102.
102. 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. Blood88:3698-3703, 1996.
103.
103. Souto JC, Coll I, Llobet D, et al: The prothrombin 20210A allele is the most prevalent genetic risk factor for venous thromboembolism in the Spanish population. Thromb Haemost80:366-369, 1998.
104.
104. Kapur RK, Mills LA, Spitzer SG, et al: A prothrombin gene mutation is significantly associated with venous thrombosis. Arterioscler Thromb Vasc Biol17:2875-2879, 1997.
105.
105. Margaglione M, Brancaccio V, Giuliani N, et al: Increased risk for venous thrombosis in carriers of the prothrombin G->A20210 gene variant. Ann Int Med129:89-93, 1998.
106.
106. Rosendaal FR, Doggen CJ, Zivelin A, et al: Geographic distribution of the 20210 G to A prothrombin variant. Thromb Haemost79:706-708, 1998.
107.
107. Zivelin A, Rosenberg N, Faier S, et al: A single genetic origin for the common prothrombotic G20210A polymorphism in the prothrombin gene. Blood92:1119-1124, 1998.
108.
108. Hillarp A, Zoller B, Svensson PJ, et al: The 20210 A allele of the prothrombin gene is a common risk factor among Swedish outpatients with verified deep venous thrombosis. Thromb Haemost78:990-992, 1997.
109.
109. Soria JM, Almasy L, Souto JC, et al: Linkage analysis demonstrates that the prothrombin G20210A mutation jointly influences plasma prothrombin levels and risk of thrombosis. Blood95:2780-2785, 2000.
110.
110. Gehring NH, Frede U, Neu-Yilik G, et al: Increased efficiency of mRNA 3' end formation: a new genetic mechanism contributing to hereditary thrombophilia. Nat Genet28:389-392, 2001.
111.
111. Carter AM, Sachchithananthan M, Stasinopoulos S, et al: Prothrombin G20210A is a bifunctional gene polymorphism. Thromb Haemost87:846-l853, 2002.
112.
112. Lopaciuk S, Bykowska K, Kwiecinski H, et al: Factor V Leiden, prothrombin gene G20210A variant, and methylenetetrahydrofolate reductase C677T genotype in young adults with ischemic stroke. Clin Appl Thromb Hemostas7:346-350, 2001.
113.
113. Lichy C, Reuner KH, Buggle F, et al: Prothrombin G20210A mutation, but not factor V Leiden, is a risk factor in patients with persistent foramen ovale and otherwise unexplained cerebral ischemia. Cerebrovasc Dis16:83-87, 2003.
114.
114. Durante-Mangoni E, Davies GJ, Ahmed N, et al: The prothrombin G20210A polymorphism in patients with myocardial infarction. Blood Coag Fibrinolysis13:603-608, 2002.
115.
115. Ridker PM, Hennekens CH, Miletich JP: G20210A mutation in prothrombin gene and risk of myocardial infarction, stroke, and venous thrombosis in a large cohort of US men. Circulation99:999-1004, 1999.
116.
116. Ridker PM, Goldhaber SZ, Danielson E, et al, PREVENT Investigators: Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med348:1425-1434, 2003.
117.
117. Kearon C, Ginsberg JS, Kovacs MJ, et al: Extended Lowintensity Anticoagulation for Thrombo-Embolism Investigators. Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for longterm prevention of recurrent venous thromboembolism. N Engl J Med349:631-639, 2003.
118.
118. Mangoni AA, Jackson SH: Homocysteine and cardiovascular disease: current evidence and future prospects. [comment]. [Review] [101 refs]Am J Med112:556-565, 2002.
119.
119. Falcon CR, Cattaneo M, Panzeri D, et al: High prevalence of hyperhomocyst(e)inemia in patients with juvenile venous thrombosis. Arterioscler Thromb14:1080-1083, 1994.
120.
120. den Heijer M, Blom HJ, Gerrits WB, et al: Is hyperhomocysteinaemia a risk factor for recurrent venous thrombosis?Lancet345:882-885, 1995.
121.
121. den Heijer M, Koster T, Blom HJ, et al: Hyperhomocysteinemia as a risk factor for deep-vein thrombosis. N Engl J Med334:759-762, 1996.
122.
122. Keijzer MB, den Heijer M, Blom HJ, et al: Interaction between hyperhomocysteinemia, mutated methylenetetrahydrofolate reductase (MTHFR) and inherited thrombophilic factors in recurrent venous thrombosis. Thromb Haemost88:723-728, 2002.
123.
123. Sunder-Plassmann G, Fodinger M: Genetic determinants of the homocysteine level. Kid Int Suppl84:S141-S144, 2003.
124.
124. Frosst P.Blom HJ, Milos R, et al: A candidate genetic risk factor for vascular disease: A common mutation in methylenetetrahydrofolate reductase. Nat Genet10:111-113, 1995.
125.
125. Starkebaum G, Harlan JM: Endothelial cell injury due to copper-catalyzed hydrogen peroxide generation from homocysteine. J Clin Invest77(4):1370-1376, 1986.
126.
126. Heinecke JW: Biochemical evidence for a link between elevated levels of homocysteine and lipid peroxidation in vivo. Curr Atheroscler Rep1:87-89, 1999.
127.
127. Lentz SR, Sadler JE: Inhibition of thrombomodulin surface expression and protein C activation by the thrombogenic agent homocysteine. J Clin Invest88:1906-1914, 1991.
128.
128. Midorikawa S.Sanada H, Hashimoto S, et al: Enhancement by homocysteine of plasminogen activator inhibitor-1 gene expression and secretion from vascular endothelial and smooth muscle cells. Biochem Biophys Res Commun272:182-185, 2000.
129.
129. Pruefer D, Scalia R, Lefer AM: Homocysteine provokes leukocyte-endothelium interaction by downregulation of nitric oxide. Gen Pharmacol33:487-498, 1999.
130.
130. Upchurch GR Jr, Welch GN, Fabian AJ, et al: Homocyst(e)ine decreases bioavailable nitric oxide by a mechanism involving glutathione peroxidase. J Biol Chem272:17012-17017, 1997.
131.
131. Bray PF: Integrin polymorphisms as risk factors for thrombosis. Thromb Haemost82:337-344, 1999.
132.
132. Fuster V, Lewis A: Conner Memorial Lecture. Mechanisms leading to myocardial infarction: insights from studies of vascular biology. Circulation90:2126-21246, 1994.
133.
133. Peerschke EIB, Lopez JA: Platelet membranes and receptors. In Loscalzo J, Schafer AI (eds): Thrombosis and Hemorrhage, 2nd ed.Williams and Wilkins, Baltimore, pp 229-260, 1998.
134.
134. Gonzalez-Conejero R, Lozano ML, Rivera J, et al: Polymorphisms of platelet membrane glycoprotein Ib associated with arterial thrombotic disease. Blood92:2771-2776, 1998.
135.
135. Murata M, Matsubara Y, Kawano K, et al: Coronary artery disease and polymorphisms in a receptor mediating shear stress-dependent platelet activation. Circulation96:3281-3286, 1997.
136.
136. Carlsson LE, Greinacher A, Spitzer C, et al: Polymorphisms of the human platelet antigens HPA-1, HPA-2, HPA-3, and HPA-5 on the platelet receptors for fibrinogen (GPIIb/IIIa), von Willebrand factor (GPIb/IX), and collagen (GPIa/IIa) are not correlated with an increased risk for stroke. Stroke28:1392-1395, 1997.
137.
137. Kunicki TJ, Orchekowski R, Annis D, et al: Variability of integrin alpha 2 beta 1 activity on human platelets. Blood82:2693-2703, 1993.
138.
138. Kunicki TJ, Kritzik M, Annis DS, et al: Hereditary variation in platelet integrin alpha 2 beta 1 density is associated with two silent polymorphisms in the alpha 2 gene coding sequence. Blood89:1939-1943, 1997.
139.
139. Kritzik M, Savage B, Nugent DJ, et al: Nucleotide polymorphisms in the alpha2 gene define multiple alleles that are associated with differences in platelet alpha2 betal density. Blood12:2382-2388, 1998.
140.
140. Santoso S, Kunicki TJ, Kroll H, et al: Association of the platelet glycoprotein Ia C807T gene polymorphism with nonfatal myocardial infarction in younger patients. Blood93:2449-2453, 1999.
141.
141. Carlsson LE, Santoso S, Spitzer C, et al: The alpha2 gene coding sequence T807/A873 of the platelet collagen receptor integrin alpha2betal might be a genetic risk factor for the development of stroke in younger patients. Blood93:3583-3586, 1999.
142.
142. Di Paola J, Federici AB, Mannucci PM, et al: Low platelet alpha2betal levels in type I von Willebrand disease correlate with impaired platelet function in a high shear stress system. Blood93:3578-3582, 1999.
143.
143. Nieswandt B, Bergmeier W, Schulte V, et al: Expression and function of the mouse collagen receptor glycoprotein VI is strictly dependent on its association with the FcRgamma chain. J Biol Chem275:23998-24002, 2000.
144.
144. Watson S, Berlanga O, Best D, et al: Update on collagen receptor interactions in platelets: is the two-state model still valid?. Platelets11:252-258, 2000.
145.
145. Furihata K, Clemetson KJ, Deguchi H, et al: Variation in human platelet glycoprotein VI-specific prothrombinase activity. Arterioscl Thromb Vasc Biol21:1857-1863, 2001.
146.
146. Croft SA, Samani NJ, Teare MD, et al: Novel platelet membrane glycoprotein VI dimorphism is a risk factor for myocardial infarction. Circulation104:1459-1463, 2001.
147.
147. Michelson AD, Furman MI, Goldschmidt-Clermont P, et al: Platelet GP IIIa P1(A) polymorphisms display different sensitivities to agonists. Circulation101:1013-1018, 2000.
148.
148. Feng D, Lindpaintner K, Larson MG, et al: Increased platelet aggregability associated with platelet GPIIIa PIA2 polymorphism: the Framingham Offspring Study. Arterioscl Thromb Vasc Biol19:1142-1147, 1999.
149.
149. Goodall AH, Curzen N, Panesar M, et al: Increased binding of fibrinogen to glycoprotein IIIa-proline33 (HPA-lb, P1A2, Zwb) positive platelets in patients with cardiovascular disease. Eur Heart J20:742-747, 1999.
150.
150. Bennett JS, Catella-Lawson F, Rut AR, et al: Effect of the Pl(A2) alloantigen on the function of beta(3)-integrins in platelets. Blood97:3093-3009, 2001.
151.
151. Vijayan KV, Goldschmidt-Clermont PJ, Roos C, et al: The Pl(A2) polymorphism of integrin beta(3) enhances outside-in signaling-and adhesive functions. J Clin Invest105:793-802, 2000.