Abstract
This review summarizes recent information about the major thrombophilic conditions, their clinical relevance, and practical aspects pertaining to testing for these thrombophilias, such as when to test and what assays are appropriate. Conditions covered include factor V Leiden, prothrombin 20210 mutation, proteins C and S, antithrombin, antiphospholipid antibodies, homocysteine, and methylene-tetrahydrofolate-reductase enzyme mutation. Additional comments focus on education of patients and educational resources for patients, such as the National Alliance for Thrombosis and Thrombophilia (www.nattinfo.org).
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Juul K, Tybjaerg-Hansen A, Schnohr P, Nordestgaard BG. Factor V Leiden and the risk for venous thromboembolism in the adult Danish population. Ann Intern Med 2004;140(5):330–337.
Marchetti M, Pistorio A, Barosi G. Extended anticoagulation for prevention of recurrent venous thromboembolism in carriers of factor V Leiden—cost-effectiveness analysis. Thromb Haemost 2000;84(5):752–757.
Buller HR, Agnelli G, Hull RD, Hyers TM, Prins MH, Raskob GE. Antithrombotic therapy for venous thromboembolic disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.Chest2004;126(3 Suppl):401S–28S.
Sampram ES, Lindblad B, Dahlback B. Activated protein C resistance in patients with peripheral vascular disease. J Vasc Surg 1998;28(4):624–9.
Van Cott EM, Soderberg BL, Laposata M. Activated protein C resistance, the factor V Leiden mutation, and a laboratory testing algorithm. Arch Path Lab Med 2002;126(5):577–582.
Tripodi A, Peyvandi F, Chantarangkul V, Menegatti M, Mannucci PM. Relatively poor performance of clinical laboratories for DNA analyses in the detection of two thrombophilic mutations—a cause for concern. Thromb Haemost 2002;88(4):690–691.
Libby E, Booker JK, Gulley ML, Garcia D, Moll S. False Negative Factor V Leiden Genetic Testing in a Patient with Recurrent Deep Venous Thrombosis. Am J Hematol 2006:in press.
Poort SR, Rosendaal FR, 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;88:3698–3703.
Rosendaal FR, Doggen CJ, Zivelin A, et al. Geographic distribution of the 20210 G to A prothrombin variant. Thromb Haemost 1998;79(4):706–708.
Dilley A, Austin H, Hooper WC, et al. Prevalence of the prothrombin 20210 G-to-A variant in blacks: infants, patients with venous thrombosis, patients with myocardial infarction, and control subjects. J Lab Clin Med 1998;132(6):452–455.
Griffin JH, Evatt B, Zimmerman TS, Kleiss AJ, Wideman C. Deficiency of proteinC in congenital thrombotic disease. J Clin Invest 1981;68(5):1370–1373.
Tait RC, Walker ID, Reitsma PH, et al. Prevalence of protein C deficiency in the healthy population. Thromb Haemost 1995;73(1):87–93.
Sakata T, Kario K, Katayama Y, Matsuyama T, Kato H, Miyata T. Studies on congenital protein C deficiency in Japanese: prevalence, genetic analysis, and relevance to the onset of arterial occlusive diseases. Semin Thromb Hemost 2000;26(1):11–16.
Allaart CF, Poort SR, Rosendaal FR, Reitsma PH, Bertina RM, Briet E. Increased risk of venous thrombosis in carriers of hereditary protein C deficiency defect. Lancet 1993;341(8838):134–138.
Bovill EG, Bauer KA, Dickerman JD, Callas P, West B. The clinical spectrum of heterozygous protein C deficiency in a large New England kindred. Blood 1989;73(3):712–717.
O'rien AE, Tate GM, Shiach C. Evaluation of protein C and protein S levels during oral anticoagulant therapy. Clin Lab Haematol 1998;20(4):245–252.
Gandrille S, Borgel D, Sala N, et al. Protein S deficiency: a database of mutations—summary of the first update. Thromb Haemost 2000;84(5):918.
Dykes AC, Walker ID, McMahon AD, Islam SI, Tait RC. 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 Haematol 2001;113(3);636–641.
Koster T, Rosendaal FR, 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(10):2756–2761.
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 Haemost 1999;82(3):1093–1096.
Simmonds RE, Ireland H, Lane DA, Zoller B, Garcia de Frutos P, Dahlback B. Clarification of the risk for venous thrombosis associated with hereditary protein S deficiency by investigation of a large kindred with a characterized gene defect. Ann Intern Med 1998;128(1):8–14.
Makris M, Leach M, Beauchamp NJ, et al. Genetic analysis, phenotypic diagnosis, and risk of venous thrombosis in families with inherited deficiencies of protein S. Blood 2000;95(6):1935–1941.
Boyer-Neumann C, Bertina RM, Tripodi A, et al. Comparison of functional assays for protein S: European collaborative study of patients with congenital and acquired deficiency. Thromb Haemost 1993;70(6):946–950.
Egeberg O. Inherited antithrombin deficiency causing thrombophilia. Thromb Diath Haemorrh 1965;13:516–530.
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 Haemost 1997;77(1):197–211.
Mateo J, Oliver A, Borrell M, Sala N, Fontcuberta J. Increased risk of venous thrombosis in carriers of natural anticoagulant deficiencies. Results of the family studies of the Spanish Multicenter Study on Thrombophilia (EMET study). Blood Coag Fibrinol 1998;9(1):71–78.
Demers C, Ginsberg JS, Hirsh J, Henderson P, Blajchman MA. Thrombosis in antithrombin-III-deficient persons. Report of a large kindred and literature review. Ann Intern Med 1992;116(9):754–761.
Heijboer H, Brandjes DP, Buller 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(22):1512–1516.
Wilson WA, Gharavi AE, Koike T, et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop. Arthritis Rheumatism 1999;42(7):1309–1311.
Khamashta MA, Guadrado MJ, Mujic F, Taub NA, Hunt BJ, Hughes GRV. The management of thrombosis in the antiphospholipid-antibody syndrome. N Engl J Med 1995;332:993–997.
Crowther MA, Ginsberg JS, Julian J, et al. A Comparison of Two Intensities of Warfarin for the Prevention of Recurrent Thrombosis in Patients with the Antiphospholipid Antibody Syndrome. N Engl J Med 2003;349(12):1133–1138.
Brey RL. Management of the neurological manifestations of APS—what do the trials tell us? Thromb Res 2004;114(5–6):489–499.
Moll S, Ortel TL. Monitoring warfarin therapy in patients with lupus anticoagulants. Ann Intern Med 1997;127:177–185.
Perry SL, Samsa GP, Ortel TL. Perry SL, P. SG, L. OT. Point of care monitoring of the international normalized ratio in patients with antiphospholipid antibodies. Blood 2004;104:513a.
Wobbleton D, Misita CP, Bryant B, Malone R, Musty M, Moll S. INR Determination By Plasma-Based Methods Versus Point-Of-Care Instruments In Patients With Antiphospholipid Antibody Syndrome on Anticoagulants (abstract). J Thromb Haemost July 2005.
Ray JG, Shmorgun D, Chan WS. Common C677T polymorphism of the methylene-tetrahydrofolate reductase gene and the risk of venous thromboembolism: meta-analysis of 31 studies. Pathophysiol Haemost Thromb 2002;32(2):51–58.
Klerk M, Verhoef P, Clarke R, Blom HJ, Kok FJ, Schouten EG. MTHFR 677CT polymorphism and risk of coronary heart disease: a meta-analysis. Jama 2002;288(16):2023–2031.
Frederiksen J, Juul K, Grande P, et al. Methylene-tetrahydrofolate reductase polymorphism (C677T), hyperhomocysteinemia, and risk of ischemic cardiovascular disease and venous thromboembolism: prospective and case-control studies from the Copenhagen City Heart Study. Blood 2004;104(10):3046–3051.
Toole JF, Malinow MR, Chambless LE, et al. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. Jama 2004;291(5): 565–575.
Bos MJ, den Heijer M, Willems H, et al. Homocysteine Lowering by Vitamins and the Secondary Prevention of Deep-Vein Thrombosis and Pulmonary Embolism. A First Randomized, Placebo-Controlled, double-Blind Trial. Blood 2004;104:142a–143a.
Hellmann EA, Leslie ND, Moll S. Knowledge and educational needs of individuals with the factor V Leiden mutation. J Thromb Haemost 2003;1(11):2335–2339.
Ornstein DL, Cushman M. Cardiology patient page. Factor V Leiden. Circulation 2003;107(15):e94–97.
Varga EA, Moll S. Cardiology patient pages. Prothrombin 20210 mutation (factor II mutation). Circulation 2004;110(3):e15–18.
Varga EA, Sturm AC, Misita CP, Moll S. Cardiology patient pages. Homocysteine and MTHFR mutations: relation to thrombosis and coronary artery disease. Circulation 2005;111(19):e289–293.
Misita CP, Moll S. Antiphospholipid Antibodies. Circulation 2005;112:e39–44.
Chitolie A, Lawrie AS, Mackie IJ, Harrison P, Machin SJ. The impact of oral anticoagulant therapy, factor VIII level and quality of factor V-deficient plasma on three commercial methods for activated protein C resistance. Blood Coag Fibrinol 2004;12(3):179–186.
Paramsothy K. Prevalence of Antiphospholipid Antibodies in Idiopathic Venous Thromboembolism. Blood 2004;104:153a.
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Moll, S. Thrombophilias—Practical Implications and Testing Caveats. J Thromb Thrombolysis 21, 7–15 (2006). https://doi.org/10.1007/s11239-006-5570-0
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DOI: https://doi.org/10.1007/s11239-006-5570-0