Laboratory investigation of thrombophilia is aimed at detecting the well-established hereditary and acquired causes of venous thromboembolism, including activated protein C resistance/factor V Leiden mutation, prothrombin G20210A mutation, deficiencies of the physio - logical anticoagulants antithrombin, protein C and protein S, the presence of antiphospholipid antibodies and increased plasma levels of homocysteine and coagulation factor VIII. In contrast, investigation of dysfibrinogenemia, a very rare thrombophilic risk factor, should only be considered in a patient with evidence of familial or recurrent thrombosis in the absence of all evaluated risk factors mentioned above. At this time, thrombophilia investigation is not recommended for other potential hereditary or acquired risk factors whose association with increased risk for thrombosis has not been proven sufficiently to date. In order to ensure clinical relevance of testing and to avoid any misinterpretation of results, laboratory investigation of thrombophilia should always be performed in accordance with the recommended guidelines on testing regarding the careful selection of patients, time of testing and assays and assay methods used. The aim of this review is to summarize the most important aspects on thrombophilia testing, including whom and when to test, what assays and assay methods to use and all other variables that should be considered when performing laboratory investigation of thrombophilia.
2. Cohen AT Agnelli G Anderson F Arcelus JI Bergqvist D Brecht JG et al. Venous thromboembolism (VTE) in Euro pe. The number of VTE events and associated mor bidity and mortality. Thromb Haemost 2007; 98: 756-64.
3. Bronic A. Thromboembolic diseases as biological and clinical syndrome - role of the Mediterranean League against Thromboembolic Diseases. Biochem Med 2010; 20: 9-12.
4. McKenzie SB Clare CN Smith LA Lee Sang JE. Laboratory test utilization in the diagnosis of hypercoagulability. Clin Lab Sci 2000; 13: 215-21.
5. Somma J Sussman I Rand JH. An evaluation of thrombophilia screening in an urban tertiary care medical center. Am J Clin Pathol 2006; 126: 120-7.
6. Jackson BR Holmes K Phansalkar A Rodgers GM. Testing for hereditary thrombophilia: a retrospective analysis of testing referred to a national laboratory. BMC Clin Pathol 2008; 8: 3.
7. Carraro P. European Communities Confederation of Clinical Chemistry and Laboratory Medicine (EC4) Work ing Group on Guidelines for Investigation of Disease. Guidelines for the laboratory investigation of inherited thrombophilias. Recommendations for the first level clinical laboratories. Clin Chem Lab Med 2003; 41: 382-91.
8. Mannucci PM. Laboratory detection of inherited thrombophilia: a historical perspective. Semin Thromb Hemost 2005; 31: 5-10.
9. Nicolaides AN Breddin HK Carpenter P Coccheri S Conard J De Stefano V et al. European Genetics Foundation Cardiovascular Disease Educational and Research Trust International Union of Angiology Mediterranean League on Thromboembolism. Thrombophilia and venous thromboembolism. International consensus statement. Guidelines according to scientific evidence. Int Angiol 2005; 24: 1-26.
10. Baglin T Gray E Greaves M Hunt BJ Keeling D Machin S et al. Clinical guidelines for testing for heritable thrombophilia. Br J Haematol 2010; 149: 209-20.
11. College of American Pathologists Consensus Conference XXXVI: Diagnostic issues in thrombophilia. Arch Pathol Lab Med 2002; 126: 1277-433.
12. Rosendaal FR. Venous thrombosis: the role of genes environment and behaviour. Hematology 2005; 1: 1-12.
13. Previtali E Bucciarelli P Passamonti SM Martinelli I. Risk factors for venous and arterial thrombosis. Blood Transfus 2011; 9: 120-38.
14. Lippi G Franchini M. Pathogenesis of venous thromboembolism: when the cup runneth over. Semin Thromb Hemost 2008; 34: 747-61.
15. Brouwer JL Veeger NJGM Kluin-Nelemans HC van der Meer J. The pathogenesis of venous thromboembolism: evidence of multiple interrelated causes. Ann Intern Med 2006; 145: 807-15.
16. Ridker PM Glynn RJ Miletich JP Goldhaber SZ Stampfer MJ Hennekens CH. Age-specific incidence rates of venous thromboembolism among heterozygous carriers of factor V Leiden mutation. Ann Intern Med 1997; 126: 528-31.
17. De Stefano V Rossi E Paciaroni K D’Orazio A Cina G Marchitelli E et al. Different circumstances of the first venous thromboembolism among younger or older he terozygous carriers of the G20210A polymorphism in the prothrombin gene. Haematologica 2003; 88: 61-6.
18. Tripodi A. Laboratory diagnosis of thrombophilic states: where do we stand? Pathophysiol Haemost Thromb 2002; 32: 245-8.
19. Martinelli I Mannucci PM De Stefano V Taioli E Rossi V Crosti F et al. Different risks of thrombosis in four coagulation defects associated with inherited thrombophilia: a study of 150 families. Blood 1998; 92: 1793-9.
20. Morris JG Singh S Fisher M. Testing for inherited thrombophilias in arterial stroke: can it cause more harm than good? Stroke 2010; 41: 2985-90.
21. Boekholdt SM Kramer MH. Arterial thrombosis and the role of thrombophilia. Semin Thromb Haemost 2007; 33: 588-96.
22. Urbanus RT Siegerink B Roest M Rosendaal FR De Groot PG Algra A. Antiphospholipid antibodies and risk of myocardial infarction and ischaemic stroke in young women in the RATIO study: a case-control study. Lancet Neurol 2009; 8: 998-1005.
24. Hayes T. Dysfibrinogenemia and thrombosis. Arch Pathol Lab Med 2002; 126: 1387-90.
25. Duran R Biner B Demir M Celtik C Karasalihoglu S. Factor V Leiden mutation and other thrombophilia markers in childhood ischemic stroke. Clin Appl Thromb Hemost 2005; 11: 83-8.
26. Segev A Ellis MH Segev F Friedman Z Rechef T Sparkes JD et al. High prevalence of thrombophilia among young patients with myocardial infarction and few conventional risk factors. Int J Cardiol 2005; 98: 421-4.
27. De Stefano V Chiusolo P Paciaroni K Casorelli I Rossi E Molinari M et al. Prothrombin G20210A mutant genotype is a risk factor for cerebrovascular ischemic disease in young patients. Blood 1998; 91: 3562-5.
28. Burzotta F Paciaroni K De Stefano V Chiusolo P Manzoli A Casorelli I et al. Increased prevalence of the G20210A prothrombin gene variant in acute coronary syndromes without metabolic or acquired risk factors or with limited extent of disease. Eur Heart J 2002; 23: 26-30.
29. Manco-Johnson MJ Grabowski EF Hellgreen M Kemahli AS Massicotte MP Muntean W et al. Labo ratory testing for thrombophilia in pediatric patients. On behalf of the Subcommittee for Perinatal and Pediatric Thrombosis of the Scientific and Standard ization Committee of the International Society of Thrombosis and Haemostasis (ISTH). Throm Haemost 2002; 88: 155-6.
30. Revel-Vilk S Chan A Bauman M. Prothrombotic conditions in an unselected cohort of children with venous thromboembolic disease. J Thromb Haemost 2003; 1: 915-21.
31. Albisetti M Moeller A Waldvogel K Bernet-Buettiker V Cannizzaro V Anagnostopoulos A et al. Congenital prothrombotic disorders in children with peripheral venous and arterial thromboses. Acta Haematol 2007; 117: 149-55.
32. Raffini L Thronburg C. Testing children for inherited throm bophilia: more answers than questions. Br J Haematol 2009; 147: 277-88.
33. Thornburg CD Dixon N Paulyson-Nunez K Ortel T. Thrombophilia screening in asymptomatic children. Thromb Res 2008; 121: 597-604.
34. Brenner B 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: 1296-303.
35. Tormene D Simioni P Prandoni P Franz F Zerbinati P Tognin G et al. The incidence of venous thromboembolism in thrombophilic children: a prospective cohort study. Blood 2002; 100: 2403-5.
36. Rodger MA Walker M Wells PS. Diagnosis and treatment of venous thromboembolism in pregnancy. Best Pract Res Clin Haematol 2003; 16: 279-96.
37. Hvas AM Ingerslev J Salvig JD. Thrombophilia risk factors are associated with intrauterine fetal death and pregnancy- related venous thromboembolism. Scand J Clin Lab Invest 2009; 69: 288-94.
38. Pomp ER Lenselink AM Rosendaal FR Doggen CJ. Pregnancy the postpartum period and prothrombotic defects: risk of venous thrombosis in the MEGA study. J Thromb Haemost 2008; 6: 632-7.
39. Robertson L Greer I. Thromboembolism in pregnancy. Curr Opin Obstet Gynecol 2005; 17: 113-16.
40. Lim W Eikelboom JW Ginsberg JS. Inherited thrombophilia and pregnancy associated venous thromboembolism. Br Med J 2007; 334: 1318-21.
41. Gerhardt A Scharf RE Beckmann MW Struve S Bender HG Pillny M et al. Prothrombin and factor V Leiden mutations in women with a history of thrombosis during pregnancy and the puerperium. N Engl J Med 2000; 342: 374-80.
42. James AH Jamison MG Brancazio LR Myers ER. Venous thromboembolism during pregnancy and the postpartum period: incidence risk factors and mortality. Am J Obstet Gynecol 2006; 194: 1311-15.
43. Robertson L Wu O Langhorne P Twaddle S Clark P Lowe GD et al. Thrombophilia in pregnancy: a systematic review. Br J Haematol 2006; 132: 171-96.
44. Merriman L Greaves M. Testing for thrombophilia: an evidence-based approach. Postgrad Med J 2006; 82: 699-704.
45. Lindhoff-Last E Luxembourg B. Evidence-based indications for thrombophilia screening. Vasa 2008; 37: 19-30.
46. Lussana F Dentali F Abbate R D’Aloja E D’Angelo A De Stefano V et al. Screening for thrombophilia and antithrombotic prophylaxis in pregnancy: guidelines of the Italian Society for Haemostasis and Thrombosis (SISET). Thromb Res 2009; 124: 19-25.
47. Rey E Kahn SR David M Shrier I. Thrombophilic disorders and fetal loss: meta-analysis. Lancet 2003; 361: 901-8.
48. Howley HE Walker M Rodger MA. A systematic review of the association between factor V Leiden or prothrombin gene variant and intrauterine growth restriction. Am J Obstet Gynecol 2005; 192: 694-708.
49. Opatrny L David M Kahn SR Shrier I Rey E. Association between antiphospholipid antibodies and recurrent fetal loss in women with autoimmune disease: a meta-analysis. J Rheumatol 2006; 33: 2214-21.
50. Kupferminc MJ Eldor A Steinman N Many A Bar-Am A Jaffa A et al. Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med 1999; 340: 9-13.
51. Younis JS Brenner B Ohel G Tal J Lanir N Ben-Ami M. Activated protein C resistance and factor V Leiden mutation can be associated with first- as well as second-trimester recurrent pregnancy loss. Am J Reprod Immunol 2000; 43: 31-5.
52. Sanson BJ Friederich PW Simioni P Zanardi S Hilsman MV Girolami A et al. The risk of abortion and stillbirth in antithrombin protein C and protein S-deficient women. Thromb Haemost 1996; 75: 387-8.
53. Dizon-Towson DS Nelson LM Easton K Ward K. The factor V Leiden mutation may predispose women to severe preeclampsia. Am J Obstet Gynecol 1996; 175: 902-5.
54. Wiener-Megnagi Z Ben-Shlomo I Goldberg Y Shalev E. Resistance to activated protein C and the Leiden mutation: high prevalence in patients with abruptio placentae. Am J Obstet Gynecol 1998; 179: 1565-7.
55. Middeldorp S. Thrombophilia and pregnancy complications: cause or association? J Thromb Haemost 2007; 5: Suppl 1: 276-82.
56. De Stefano V Rossi V Paciaroni K Leone G. Screening for inherited thrombophilia: indications and therapeutic implications. Haematologica 2002; 87: 1095-108.
57. Norrie G Farquharson RG Greaves M. Screening and treatment for heritable thrombophilias in pregnancy failure: inconsistencies among UK early pregnancy units. Br J Haematol 2008; 144: 241-4.
58. Roque H Paidas MJ Funai EF Kuczynski E Lockwood CJ. Maternal thrombophilias are not associated with early pregnancy loss. Thromb Haemost 2004; 91: 290-5.
59. Rodger MA Paidas MJ Mclintock C Middeldorp S Kahn SR Martinelli I et al. Inherited thrombophilia and pregnancy complications revisited: association not proven causal and antithrombotic prophylaxis is experimental. Obstet Gynecol 2008; 112: 320-4.
60. Jordaan D Schoon MG Badenhorst PN. Thrombophilia screening in pregnancy. Obstet Gynecol Surv 2005; 60: 394-404.
61. Empson M Lassere M Craig J Scott J. Prevention of recurrent miscarriage for women with antiphospholipid antibody or lupus anticoagulant. Cohrane Database Syst Rev 2005; 2: CD002859.
62. Martinelli I Taioli E Ragni G Levi-Setti P Passamonti SM Battaglioli T et al. Embryo implantation after assisted reproductive procedures and maternal thrombophilia. Haematologica 2003; 88: 789-93.
63. Fabregues F Tassies D Reverter JC Carmona F Ordinas A Balasch J. Prevalence of thrombophilia in women with severe ovarian hyperstimulation syndrome and costeffectiveness of screening. Fertil Steril 2004; 81: 989-95.
64. Chan WS. The »ART« of thrombosis: a review of arterial and venous thrombosis in assisted reproductive technology. Curr Opin Obstet Gynecol 2009; 21: 207-18.
65. Vandenbroucke JP Rosing J Bloemenkamp KWM Middeldorp S Helmerhorst FM Bouma BN et al. Oral contraceptives and the risk of venous thrombosis. N Engl J Med 2001; 344: 1527-35.
66. Canonico M Plu-Bureau G Lowe GD Scarabin PY. Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis. Br Med J 2008; 336: 1227-31.
67. Van Hylckama Vlieg A Helmerhorst FM Vanderbroucke JP Doggen CJ Rosendaal FR. The venous thrombotic risk of oral contraceptives effects of oestrogen dose and progestogen type: results of the MEGA case-control study. BMJ 2009; 339: B2921.
68. Vandenbroucke JP Koster T Briet E Reitsma PH Bertina RM. Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation. Lancet 1994; 344: 1453-7.
69. Martinelli I Taioli E Bucciarelli P Akhavean S Mannucci PM. Interaction between the G20210A mutation of the prothrombin gene and oral contraceptive use in deep venous thrombosis. Arterioscl Thromb Vasc Biol 1999; 19: 700-3.
70. Lowe G Woodward M Vessey M Rumley A Gough P Daly E. Thrombotic variables and risk of idiopathic throm boembolism in women aged 45-64 years. Relation ship to hormone replacement therapy. Thromb Haemost 2000; 83: 530-5.
71. Heinemann LAJ Dinger JC. Range of published estimates of venous thromboembolism incidence in young women. Contraception 2007; 75: 328-36.
72. Dinger JC Heinemann LAJ Kuhl-Habich D. The safety of a drospirenone-containing oral contraceptive: final results from the European active surveillance study on oral contraceptives based on 142475 women-years of observation. Contraception 2007; 75: 344-54.
73. Trenor CC Chung RJ Michelson AD Neufeld EJ Gordon CM Laufer MR et al. Hormonal contraception and thrombotic risk: a multidisciplinary approach. Pediatrics 2011; 127: 347-57.
74. Reid RL Westhoff C Mansour D De Vries C Verhaeghe J Boschitsch E et al. Oral contraceptives and venous thromboembolism. Consensus opinion from an international workshop held in Berlin Germany in December 2009. J Fam Plann Reprod Health Care 2010; 36: 117-22.
75. Wu O Robertson L Langhorne P Twaddle S Lowe GDO Clark P et al. Oral contraceptives hormone replacement therapy thrombophilias and risk of venous thromboembolism: a systematic review. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) Study. Thromb Haemost 2005; 94: 17-25.
76. Pernod G Biron-Andreani C Morange PE Boehlen F Constans J Couturaud F et al. Recommendations on testing for thrombophilia in venous thromboembolic disease: A French consensus guideline. J Malad Vasc 2009; 34: 156-203.
77. Mohllajee AP Curtis KM Martins SL Peterson HB. Does use of hormonal contraceptives among women with thrombogenic mutations increase their risk of venous thromboembolism? Contraception 2006; 73: 166-78.
78. Rabe T Luxembourg B Ludwig M Dinger J Bauersachs R Rott H et al. Contraception and thrombophilia - A stetement from the German society for gynaecological endocrinology and reproductive medicine (DGGEF e.V.) and the professional association of German Gynaecologists (BVF e.V.). J Reproduktionsmed Endokrinol 2011; 8: Spec. Issue 1: 178-218.
79. Seligsohn U Lubetsky A. Genetic susceptibility to venous thrombosis. N Engl J Med 2001; 344: 1222-31.
80. Varga E. Inherited thrombophilia: key points for genetic counselling. J Gen Counsel 2007; 16: 261-77.
81. Vossen CY Conard J Fontcuberta J Makris M Van Der Meer FJM Pabinger G et al. Risk of a first venous thrombotic event in carriers of a familial thrombophilic defect. The European Prospective Cohort on Thrombophilia (EPCOT). J Thromb Haemost 2005; 3: 459-64.
82. Dalen JE. Should patients with venous thromboembolism be screened for thrombophilia? Am J Med 2008; 121: 458-63.
83. Eichinger S. Consequences of thrombophilia screening for life quality in women before prescription of oral contraceptives and family members of VTE patients. Hämostaseologie 2009; 29: 110-11.
84. Cohn DM Vansenne F Kaptein AA De Borgie CA Middeldorp S. The psychological impact of testing for thrombophilia: a systematic review. J Thromb Haemost 2008; 6: 1099-104.
85. Varga E. Genetic counselling for inherited thrombophilias. J Thromb Haemost 2008; 25: 6-9.
86. Green D. Genetic hypercoagulability: screening should be an informed choice. Blood 2001; 98: 20.
87. Stegnar M. Thrombophilia screening - at the right time for the right patient with a good reason. Clin Chem Lab Med 2010; 48: Suppl 1: S105-S113.
88. Selby R Geerts W. Prevention of venous thromboembolism: consensus controversies and challenges. Hematology Am Soc Hematol Educ Program 2009; 286-92.
89. Wautrecht JC. Venous thromboembolic disease: which coagulation screening for whom when? Rev Med Brux 2005; 26: S315-S9.
90. Robetorye RS Rodgers GM. Update on selected inherited venous thrombotic disorders. Am J Hematol 2001; 68: 256-68.
91. Margetić S. Diagnostic algorithm for thrombophilia screening. Clin Chem Lab Med 2010; 48: Suppl 1: S27-S39.
92. Bertina RM Koeleman BP 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: 64-7.
93. Lucotte G Mercier G. Population genetics of factor V Leiden in Europe. Blood Cells Mol Dis 2001; 27: 362-7.
94. Coppola A Tufano A Cerbone AM Di Minno G. Inherited thrombophilia: implications for prevention and treatment of venous thromboembolism. Semin Thromb Hemost 2009; 35: 683-94.
95. Clark P Walker ID. The phenomenon known as acquired activated protein C resistance. Br J Haematol 2001; 115: 767-73.
96. Remkova A. Diagnostic approach to hypercoagulable states. Bratisl Lek Listy 2006; 107: 292-5.
97. Graff LL Welsh CH Qamar Z Marlar RA. Activated protein C resistance assay detects thrombotic risk factors other than factor V Leiden. Am J Clin Pathol 2003; 119: 52-60.
98. Zangari M Saghafifar F Anaissie E Badros A Desikan R Fassas A et al. Activated protein C resistance in the absence of factor V Leiden mutation is a common finding in multiple myeloma and is associated with an increased risk of thrombotic complications. Blood Coag Fibrinolysis 2002; 13: 187-92.
99. Khor B van Cott EM. Laboratory evaluation of hypercoagulability. Clin Lab Med 2009; 29: 339-66.
100. Dahlback B Carlsson M Svensson PJ. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C. Proc Natl Acad Sci USA 1993; 90: 1004-8.
101. 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: 3698-703.
102. Zivelin A Mor-Cohen R Kovalsky V Kornbrot N Conard J Peyvandi F et al. Prothrombin 20210G>A is an ancestral prothrombotic mutation that occurred in whites approximately 24.000 years ago. Blood 2006; 107: 4666-8.
103. Van der Meer FJ Koster T Vandenbroucke JP Briët E Rosendaal FR. The Leiden Thrombopilia Study (LETS). Thromb Haemost 1997; 78: 631-5.
104. Gehring NH Frede U Neu-Yilik G Hundsdoerfer P Vetter B Hentze MW et al. Increased efficiency of mRNA 3’ end formation: a new genetic mechanism contributing to hereditary thrombophilia. Nat Genet 2001; 28: 389-92.
105. Grunewald M Germowitz A Beneke H Guethner C Griesshammer M. Coagulation II activity determination is not useful as a screening tool for the G20210A prothrombin gene allele (letter). Thromb Haemost 2000; 84: 141-2.
106. Kottke-Marchant K Duncan A. Antithrombin deficiency: issues in laboratory diagnosis. Arch Pathol Lab Med 2002; 126: 1367-75.
107. Spek CA Reitsma PH. Genetic risk factors for venous thrombosis. Molec Genet Metab 2000; 71: 51-61.
108. Jennings I Cooper P. Screening for thrombophilia: a laboratory perspective. Br J Biomed Sc 2003; 60: 39-51.
109. Picard V Nowak-Göttl U Biron-Andreani C Fouassier M Frere C Goualt-Heilman M et al. Molecular bases of antithrombin deficiency: twenty-two novel mutations in the antithrombin gene. Hum Mutat 2006; 27: 600.
110. Rossi E Chiusolo P Za T Marietti S Ciminello A Leone G et al. Report of a novel kindred with antithrombin heparin-binding site variant (47 Arg to His): demand for an automated progressive antithrombin assay to detect molecular variants with low thrombotic risk. Thromb Haemost 2007; 98: 695-7.
111. Cumming AM Shiach CR. The investigation and management of inherited thrombophilia. Clin Lab Haem 1999; 21: 77-92.
112. Castoldi E Hackeng TM. Regulation of coagulation by protein S. Curr Opin Hematol 2008; 15: 529-36.
113. Goodwin AJ Rosendaal FR Kottke-Marchant K Bovill E. A review of the technical diagnostic and epidemiologic considerations for protein S assays. Arch Pathol Lab Med 2002; 126: 1349-66.
114. Van Cott EM Ledford-Kraemer M Meijer P Nichols WL Johnson SM Perrschke EI. Protein S assays. Am J Clin Pathol 2005; 123: 778-85.
115. Miyakis S Lockshin MD Atsumi T Branch DW Brey RL Cervera R et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006; 4: 295-306.
116. Bećarević M Ignjatović S Majkić-Singh N. Apoptosis annexin A5 and anti-annexin as antibodies in the antiphospholipid syndrome. J Med Biochem 2013; 32: 89-95.
117. Pengo V Tripodi A Reber G Rand JG Ortel TL Galli M et al. Update of the guidelines for lupus anticoagulant detection. J Thromb Haemost 2009; 7: 1737-40.
118. Brandt JT Triplett DA Alving B Scharrer IM. Criteria for the diagnosis of lupus anticoagulants: an update. Thromb Haemost 1995; 74: 1185-90.
119. Galli M. Clinical utility of laboratory tests used to identify antiphospholipid antibodies and to diagnose the antiphospholipid syndrome. Semin Thromb Hemost 2008; 34: 329-34.
120. Reber G de Moerloose P. Anti-beta-2-glycoprotein I antibodies - when and how should they be measured? Thromb Res 2004; 114: 527-31.
121. Marai I Gillburd B Blank M Shoenfeld Y. Anti-cardiolipin and anti-beta2-glycoprotein I (beta2GP-I) antibody assays as screening for anti-phospholipid syndrome. Hum Antibodies 2003; 12: 57-62.
122. Den Heijer M Koster T Blom HJ Bos GMJ Briet E Reitsma PH et al. Hyperhomocysteinemia as a risk factor for deep-vein thrombosis. N Engl J Med 1996; 334: 759-62.
123. Debreceni L. Homocysteine - a risk factor for atherosclerosis. Orv Hetil 2001; 142: 1439-44.
124. Milosević-Tošić M Borota J. Hyperhomocysteinemia - a risk factor for development of occlusive vascular diseases. Med Pregl 2002; 55: 385-91.
125. Falcon CR Cattaneo M Penzeri D Martinelli I Mannucci PM. High prevalence of hyperhomocysteinemia in patients with juvenile venous thrombosis. Arterioscler Thromb 2000; 14: 1080-3.
126. Guba S Fonseca V Link L. Hyperhomocysteinemia and thrombosis. Semin Thromb Hemost 1999; 253: 291-309.
127. Bezemer ID Doggen CJ Vos HL Rosendaal FR. No association between the common MTHFR 677C->T polymorphism and venous thrombosis: results from the MEGA study. Arch Intern Med 2007; 167: 497-501.
128. Koster T Blann AD Briet E Vanderbroucke JP Rosendaal FR. Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis. Lancet 1995; 345: 152-5.
129. O’Donnell J Mumford AD Manning RA Laffan M. Elevation of FVIII:C in venous thromboembolism is persistent and independent of the acute phase response. Thromb Haemost 2000; 83: 10-13.
130. Kraaijenhagen RA in’t Anker PS Koopman MMW Reitsma PH Prins MH van den Ende A et al. High plasma concentration of factor VIIIc is a major risk factor for venous thromboembolism. Thromb Haemost 2000; 83: 5-9.
131. Kyrle PA Minar E Hirschl M Bialonczyk C Stain M Schneider B et al. High plasma levels of factor VIII and the risk of recurrent venous thromboembolism. N Eng J Med 2000; 343: 457-62.
132. Kamphuisen PW Houwing-Duistermaat JJ van Houwelingen HC Eikenboom JCJ Bertina RM Rosendaal FR. Familial clustering of factor VIII and von Willebrand factor levels. Thromb Haemost 1998; 79: 323-7.
133. Bank I Libourel EJ Middeldorp S Hamulyak K van Pampus EC Koopman MM et al. Elevated levels of FVIII:C within families are associated with an increased risk for venous and arterial thrombosis. J Thromb Haemost 2005; 3: 79-84.
134. Cunningham MT Brandt JT Laposata M Olson JD. Laboratory diagnosis of dysfibrinogenemia. Arch Pathol Lab Med 2002; 126: 499-505.
135. Haverkate F Samama M. Familial dysfibrinogenemia and thrombophilia. Report on a study of the SSC subcommittee on fibrinogen. Thromb Haemost 1995; 73: 151-61.
136. Moll S. Testing for thrombophilias. Clin Adv Hematol Oncol 2008; 6: 646-9.
137. Andrew M Paes B Milner R Johnston M Mitchell L Tollefsen DM et al. Development of the human coagulation system in the full-term infant. Blood 1987; 70: 165-72.
138. Andrew M Vegh P Johnston M Bowker J Ofosu F Mitchell L. Maturation of the hemostatic system during childhood. Blood 1992; 80: 1998-2005.
139. Monagle P Barnes C Ignjatovic V Furmedge J Newall F Chan A et al. 139. Developmental haemostasis. Impact for clinical haemostasis laboratories. Thromb Haemost 2006; 95: 362-72.
140. Majkić-Singh N Šumarac Z. Quality Indicators of the Pre-Analytical Phase. J Med Biochem 2012; 31: 174-83.
141. Favaloro EJ McDonald D Lippi G. Laboratory investigation of thrombophilia: the good the bad and the ugly. Semin Thromb Hemost 2009; 35: 695-710.