Subscribe to RSS
DOI: 10.1055/s-0028-1103366
Social and Ethical Controversies in Thrombophilia Testing and Update on Genetic Risk Factors for Venous Thromboembolism
Publication History
Publication Date:
28 November 2008 (online)
ABSTRACT
Over the past 20 years, the landscape with respect to evaluation of thrombophilia, the inherited or acquired tendency to develop venous thromboembolism, has changed dramatically. Increased knowledge regarding the contribution of genetic predisposition to thrombosis has raised several questions regarding screening, diagnosis, and management. In this review, we will examine these issues while providing an update on genetic testing for inherited thrombotic disorders.
KEYWORDS
Thrombophilia - thrombosis - factor V Leiden - prothrombin - genetic testing
REFERENCES
- 1 Buchanan G S, Rodgers G M, Ware Branch D. The inherited thrombophilias: genetics, epidemiology, and laboratory evaluation. Best Pract Res Clin Obstet Gynaecol. 2003; 17 397-411
- 2 Machin S J. Pros and cons of thrombophilia testing: cons. J Thromb Haemost. 2003; 1 412-413
- 3 Martinelli I. Pros and cons of thrombophilia testing: pros. J Thromb Haemost. 2003; 1 410-411
- 4 Coppens M, van Mourik J A, Eckmann C M, Buller H R, Middeldorp S. Current practise of testing for inherited thrombophilia. J Thromb Haemost. 2007; 5 1979-1981
- 5 Martinelli I. Rebuttal to: Pros and cons of thrombophilia testing—cons. J Thromb Haemost. 2003; 1 1311-1312
- 6 Bauer K A. Management of thrombophilia. J Thromb Haemost. 2003; 1 1429-1434
- 7 Kearon C. Indefinite anticoagulation after a first episode of unprovoked venous thromboembolism: yes. J Thromb Haemost. 2007; 5 2330-2335
- 8 Caprini J A, Glase C J, Anderson C B, Hathaway K. Laboratory markers in the diagnosis of venous thromboembolism. Circulation. 2004; 109 I4-I18
- 9 Wu O, Robertson L, Twaddle S et al.. Screening for thrombophilia in high-risk situations: systematic review and cost-effectiveness analysis. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) study. Health Technol Assess. 2006; 10 1-110
- 10 College of American Pathologists Consensus Conference XXXVI: Diagnostic Issues in Thrombophilia. Arch Pathol Lab Med. 2002; 126 1277-1433
- 11 Grody W W, Griffin J H, Taylor A K, Korf B R, Heit J A. American College of Medical Genetics consensus statement on factor V Leiden mutation testing. Genet Med. 2001; 3 139-148
- 12 Nicolaides A N, Breddin H K, Carpenter P et al.. Thrombophilia and venous thromboembolism. International consensus statement. Guidelines according to scientific evidence. Int Angiol. 2005; 24 1-26
- 13 Geerts W H, Pineo G F, Heit J A et al.. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004; 126 338S-400S
- 14 Laberge A MPB, Hindorff L, Burke W. Use of the genetic test for factor V Leiden in practice and impact on patient management. Presented at: The Annual Meeting of The American Society of Human Genetics October 25, 2007 San Diego, CA; [abstract 813]
- 15 Bates S M, Greer I A, Hirsh J, Ginsberg J S. Use of antithrombotic agents during pregnancy: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004; 126 627S-644S
- 16 James A H, Abel D E, Brancazio L R. Anticoagulants in pregnancy. Obstet Gynecol Surv. 2006; 61 59-69
- 17 Saukko P M, Richards S H, Shepherd M H, Campbell J L. Are genetic tests exceptional? Lessons from a qualitative study on thrombophilia. Soc Sci Med. 2006; 63 1947-1959
- 18 Hellmann E A, Leslie N D, Moll S. Knowledge and educational needs of individuals with the factor V Leiden mutation. J Thromb Haemost. 2003; 1 2335-2339
- 19 Kamphuisen P W, Rosendaal F R. Thrombophilia screening: a matter of debate. Neth J Med. 2004; 62 180-187
- 20 Eichinger S, Pabinger I, Stumpflen A et al.. The risk of recurrent venous thromboembolism in patients with and without factor V Leiden. Thromb Haemost. 1997; 77 624-628
- 21 Kearon C. Initial treatment of venous thromboembolism. Thromb Haemost. 1999; 82 887-891
- 22 Lindmarker P, Schulman S, Sten-Linder M et al.. The risk of recurrent venous thromboembolism in carriers and non-carriers 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 Haemost. 1999; 81 684-689
- 23 Ridker P M, Goldhaber S Z, Danielson E et al.. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med. 2003; 348 1425-1434
- 24 Simioni P, Prandoni P, Lensing A W 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 Med. 1997; 336 399-403
- 25 De Stefano V, Martinelli I, Mannucci P M 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 Med. 1999; 341 801-806
- 26 Makris M, Rosendaal F R, Preston F E. Familial thrombophilia: genetic risk factors and management. J Intern Med Suppl. 1997; 740 9-15
- 27 Zoller B, Berntsdotter A, Garcia de Frutos P, Dahlback B. Resistance to activated protein C as an additional genetic risk factor in hereditary deficiency of protein S. Blood. 1995; 85 3518-3523
- 28 Nowak-Gottl U, Junker R, Kreuz W et al.. Risk of recurrent venous thrombosis in children with combined prothrombotic risk factors. Blood. 2001; 97 858-862
- 29 Stark J E, Kilzer W J. Venous thromboembolic prophylaxis in hospitalized medical patients. Ann Pharmacother. 2004; 38 36-40
- 30 Brill-Edwards P, Ginsberg J S, Gent M et al.. Safety of withholding heparin in pregnant women with a history of venous thromboembolism. Recurrence of Clot in This Pregnancy Study Group. N Engl J Med. 2000; 343 1439-1444
- 31 Dizon-Townson D, Miller C, Sibai B et al.. The relationship of the factor V Leiden mutation and pregnancy outcomes for mother and fetus. Obstet Gynecol. 2005; 106 517-524
- 32 Ginsberg J S, Kowalchuk G, Hirsh J, Brill-Edwards P, Burrows R. Heparin therapy during pregnancy. Risks to the fetus and mother. Arch Intern Med. 1989; 149 2233-2236
- 33 Vandenbroucke J P, Koster T, Briet E et al.. Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation. Lancet. 1994; 344 1453-1457
- 34 Martinelli I, Taioli E, Bucciarelli P, Akhavan S, Mannucci P M. Interaction between the G20210A mutation of the prothrombin gene and oral contraceptive use in deep vein thrombosis. Arterioscler Thromb Vasc Biol. 1999; 19 700-703
- 35 FDA News .FDA approves update to label on birth control patch. January 18, 2008. Available at: http://www.fda.gov/bbs/topics/NEWS/2008/NEW0178/.html Accessed November 10, 2008
- 36 Brenner B R, Nowak-Gottl U, Kosch A, Manco-Johnson M, Laposata M. Diagnostic studies for thrombophilia in women on hormonal therapy and during pregnancy, and in children. Arch Pathol Lab Med. 2002; 126 1296-1303
- 37 Bank I, Scavenius M P, Buller H R, Middeldorp S. Social aspects of genetic testing for factor V Leiden mutation in healthy individuals and their importance for daily practice. Thromb Res. 2004; 113 7-12
- 38 Reich L M, Bower M, Key N S. Role of the geneticist in testing and counseling for inherited thrombophilia. Genet Med. 2003; 5 133-143
- 39 Kitchens C S, Alving B M, Kessler C M. Consultative Hemostasis and Thrombosis. Philadelphia, PA; W.B. Saunders 2002: 181-196
- 40 Egeberg O. Inherited antithrombin deficiency causing thrombophilia. Thromb Diath Haemorrh. 1965; 13 516-530
- 41 Schafer A I, Levine M N, Konkle B A, Kearon C. Thrombotic disorders: diagnosis and treatment. Presented at: the American Society of Hematology 2003 annual conference Available at: http://asheducationbook.hematologylibrary.org
- 42 Olds R J, Lane D A, Chowdhury V et al.. Complete nucleotide sequence of the antithrombin gene: evidence for homologous recombination causing thrombophilia. Biochemistry. 1993; 32 4216-4224
- 43 Lane D A, Bayston T, Olds R J et al.. Antithrombin mutation database: 2nd (1997) update. For the Plasma presented at: the Coagulation Inhibitors Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost. 1997; 77 197-211
- 44 Bick R L. Prothrombin G20210A mutation, antithrombin, heparin cofactor II, protein C, and protein S defects. Hematol Oncol Clin North Am. 2003; 17 9-36
- 45 Hirsh J, Piovella F, Pini M. Congenital antithrombin III deficiency. Incidence and clinical features. Am J Med. 1989; 87 34S-38S
- 46 Kottke-Marchant K, Duncan A. Antithrombin deficiency: issues in laboratory diagnosis. Arch Pathol Lab Med. 2002; 126 1326-1336
- 47 Martinelli I, Mannucci P M, De Stefano V et al.. Different risks of thrombosis in four coagulation defects associated with inherited thrombophilia: a study of 150 families. Blood. 1998; 92 2353-2358
- 48 Nakase H, Kawasaki T, Itani T et al.. Budd-Chiari syndrome and extrahepatic portal obstruction associated with congenital antithrombin III deficiency. J Gastroenterol. 2001; 36 341-345
- 49 Bauer K A. Management of patients with hereditary defects predisposing to thrombosis including pregnant women. Thromb Haemost. 1995; 74 94-100
- 50 Tiede A, Tait R C, Shaffer D W et al.. Antithrombin alfa in hereditary antithrombin deficient patients: a phase 3 study of prophylactic intravenous administration in high risk situations. Thromb Haemost. 2008; 99 616-622
- 51 Crowther M A, Kelton J G. Congenital thrombophilic states associated with venous thrombosis: a qualitative overview and proposed classification system. Ann Intern Med. 2003; 138 128-134
- 52 Griffin J H, Evatt B, Zimmerman T S, Kleiss A J, Wideman C. Deficiency of protein C in congenital thrombotic disease. J Clin Invest. 1981; 68 1370-1373
- 53 Reitsma P H, Bernardi F, Doig R G 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 Haemost. 1995; 73 876-889
- 54 Franchini M, Veneri D, Salvagno G L, Manzato F, Lippi G. Inherited thrombophilia. Crit Rev Clin Lab Sci. 2006; 43 249-290
- 55 Koster T, Rosendaal F R, Briet E et al.. Protein C deficiency in a controlled series of unselected outpatients: an infrequent but clear risk factor for venous thrombosis (Leiden Thrombophilia Study). Blood. 1995; 85 2756-2761
- 56 McGehee W G, Klotz T A, Epstein D J, Rapaport S I. Coumarin necrosis associated with hereditary protein C deficiency. Ann Intern Med. 1984; 101 59-60
- 57 Schwarz H P, Fischer M, Hopmeier P, Batard M A, Griffin J H. Plasma protein S deficiency in familial thrombotic disease. Blood. 1984; 64 1297-1300
- 58 Simmonds R E, Zoller B, Ireland H et al.. Genetic and phenotypic analysis of a large (122-member) protein S-deficient kindred provides an explanation for the familial coexistence of type I and type III plasma phenotypes. Blood. 1997; 89 4364-4370
- 59 Gandrille S, Borgel D, Sala N et al.. Protein S deficiency: a database of mutations—summary of the first update. Thromb Haemost. 2000; 84 918
- 60 Bertina R M, Koeleman B P, Koster T et al.. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature. 1994; 369 64-67
- 61 Koster T, Rosendaal F R, de Ronde H et al.. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study. Lancet. 1993; 342 1503-1506
- 62 Rosendaal F R, Koster T, Vandenbroucke J P, Reitsma P H. High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance). Blood. 1995; 85 1504-1508
- 63 Rees D C, Cox M, Clegg J B. World distribution of factor V Leiden. Lancet. 1995; 346 1133-1134
- 64 Williamson D, Brown K, Luddington R, Baglin C, Baglin T, Factor V. Cambridge: a new mutation (Arg306→Thr) associated with resistance to activated protein C. Blood. 1998; 91 1140-1144
- 65 Norstrom E, Thorelli E, Dahlback B. Functional characterization of recombinant FV Hong Kong and FV Cambridge. Blood. 2002; 100 524-530
- 66 Bernardi F, Faioni E M, Castoldi E et al.. A factor V genetic component differing from factor V R506Q contributes to the activated protein C resistance phenotype. Blood. 1997; 90 1552-1557
- 67 de Visser M C, Guasch J F, Kamphuisen P W et al.. The HR2 haplotype of factor V: effects on factor V levels, normalized activated protein C sensitivity ratios and the risk of venous thrombosis. Thromb Haemost. 2000; 83 577-582
- 68 Castaman G, Faioni E M, Tosetto A, Bernardi F. The factor V HR2 haplotype and the risk of venous thrombosis: a meta-analysis. Haematologica. 2003; 88 1182-1189
- 69 Poort S R, Rosendaal F R, Reitsma P H, Bertina R M. 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 3698-3703
- 70 Kyrle P A, Mannhalter C, Beguin S et al.. Clinical studies and thrombin generation in patients homozygous or heterozygous for the G20210A mutation in the prothrombin gene. Arterioscler Thromb Vasc Biol. 1998; 18 1287-1291
- 71 Franco R F, Santos S E, Elion J, Tavella M H, Zago M A. Prevalence of the G20210A polymorphism in the 3′-untranslated region of the prothrombin gene in different human populations. Acta Haematol. 1998; 100 9-12
- 72 McGlennen R C, Key N S. Clinical and laboratory management of the prothrombin G20210A mutation. Arch Pathol Lab Med. 2002; 126 1319-1325
- 73 Haverkate F, Samama M. Familial dysfibrinogenemia and thrombophilia. Report on a study of the SSC Subcommittee on Fibrinogen. Thromb Haemost. 1995; 73 151-161
- 74 Martinez J, Ferber A. Hematology: Basic Principles and Practice. 4th ed. Philadelphia, PA; Churchill Livingstone 2005: 2097-2109
- 75 Asselta R, Duga S, Tenchini M L. The molecular basis of quantitative fibrinogen disorders. J Thromb Haemost. 2006; 4 2115-2129
- 76 Cunningham M T, Brandt J T, Laposata M, Olson J D. Laboratory diagnosis of dysfibrinogenemia. Arch Pathol Lab Med. 2002; 126 499-505
- 77 Perry I J, Refsum H, Morris R W et al.. Prospective study of serum total homocysteine concentration and risk of stroke in middle-aged British men. Lancet. 1995; 346 1395-1398
- 78 Selhub J, Jacques P F, Bostom A G et al.. Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis. N Engl J Med. 1995; 332 286-291
- 79 Stampfer M J, Malinow M R, Willett W C et al.. A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians. JAMA. 1992; 268 877-881
- 80 den Heijer M, Koster T, Blom H J et al.. Hyperhomocysteinemia as a risk factor for deep-vein thrombosis. N Engl J Med. 1996; 334 759-762
- 81 Pereira A C, Schettert I T, Morandini Filho A A, Guerra-Shinohara E M, Krieger J E. Methylenetetrahydrofolate reductase (MTHFR) c677t gene variant modulates the homocysteine folate correlation in a mild folate-deficient population. Clin Chim Acta. 2004; 340 99-105
- 82 Moll S. Thrombophilias–practical implications and testing caveats. J Thromb Thrombolysis. 2006; 21 7-15
- 83 Esfahani S T, Cogger E A, Caudill M A. Heterogeneity in the prevalence of methylenetetrahydrofolate reductase gene polymorphisms in women of different ethnic groups. J Am Diet Assoc. 2003; 103 200-207
- 84 Domagala T B, Adamek L, Nizankowska E, Sanak M, Szczeklik A. Mutations C677T and A1298C of the 5,10-methylenetetrahydrofolate reductase gene and fasting plasma homocysteine levels are not associated with the increased risk of venous thromboembolic disease. Blood Coagul Fibrinolysis. 2002; 13 423-431
- 85 Kluijtmans L A, den Heijer M, Reitsma P H et al.. Thermolabile methylenetetrahydrofolate reductase and factor V Leiden in the risk of deep-vein thrombosis. Thromb Haemost. 1998; 79 254-258
- 86 Koster T, Blann A D, Briet E, Vandenbroucke J P, Rosendaal F R. Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis. Lancet. 1995; 345 152-155
- 87 Kamphuisen P W, Houwing-Duistermaat J J, van Houwelingen H C et al.. Familial clustering of factor VIII and von Willebrand factor levels. Thromb Haemost. 1998; 79 323-327
- 88 Kamphuisen P W, Eikenboom J C, Bertina R M. Elevated factor VIII levels and the risk of thrombosis. Arterioscler Thromb Vasc Biol. 2001; 21 731-738
- 89 Girolami A, Randi M L, Gavasso S, Lombardi A M, Spiezia F. The occasional venous thromboses seen in patients with severe (homozygous) FXII deficiency are probably due to associated risk factors: a study of prevalence in 21 patients and review of the literature. J Thromb Thrombolysis. 2004; 17 139-143
- 90 Soria J M, Almasy L, Souto J C et al.. A quantitative-trait locus in the human factor XII gene influences both plasma factor XII levels and susceptibility to thrombotic disease. Am J Hum Genet. 2002; 70 567-574
- 91 Endler G, Exner M, Mannhalter C et al.. A common C→T polymorphism at nt 46 in the promoter region of coagulation factor XII is associated with decreased factor XII activity. Thromb Res. 2001; 101 255-260
- 92 Sprengers E D, Kluft C. Plasminogen activator inhibitors. Blood. 1987; 69 381-387
- 93 Eriksson P, Kallin B, van 't Hooft F M, Bavenholm P, Hamsten A. Allele-specific increase in basal transcription of the plasminogen-activator inhibitor 1 gene is associated with myocardial infarction. Proc Natl Acad Sci U S A. 1995; 92 1851-1855
- 94 Tsantes A E, Nikolopoulos G K, Bagos P G et al.. Association between the plasminogen activator inhibitor-1 4G/5G polymorphism and venous thrombosis. A meta-analysis. Thromb Haemost. 2007; 97 907-913
- 95 Endler G, Mannhalter C. Polymorphisms in coagulation factor genes and their impact on arterial and venous thrombosis. Clin Chim Acta. 2003; 330 31-55
- 96 Hoppe B, Tolou F, Dorner T, Kiesewetter H, Salama A. Gene polymorphisms implicated in influencing susceptibility to venous and arterial thromboembolism: frequency distribution in a healthy German population. Thromb Haemost. 2006; 96 465-470
- 97 Sykes T C, Fegan C, Mosquera D. Thrombophilia, polymorphisms, and vascular disease. Mol Pathol. 2000; 53 300-306
- 98 Bezemer I D, Bare L A, Doggen C J et al.. Gene variants associated with deep vein thrombosis. JAMA. 2008; 299 1306-1314
- 99 Bovill E G. Gene discovery in venous thrombosis: progress and promise. JAMA. 2008; 299 1362-1363
- 100 Adams M, Ward C, Thom J et al.. Emerging technologies in hemostasis diagnostics: a report from the Australasian Society of Thrombosis and Haemostasis Emerging Technologies Group. Semin Thromb Hemost. 2007; 33 226-234
Elizabeth A VargaM.S.
The Research Institute at Nationwide Children's Hospital
700 Children's Dr., Wexner - 4th Floor, Columbus, OH 43205
Email: Elizabeth.Varga@Nationwidechildrens.org