Update Thrombophilie

E. Lindhoff-Last; B. Luxembourg; I. Pabinger

doi:10.1055/s-0037-1617184

Hämostaseologie, Table of Contents

Hamostaseologie 2008; 28(05): 365-375
DOI: 10.1055/s-0037-1617184

Hämostaseologie

Schattauer GmbH

Update Thrombophilie

Update Thrombophilia

Authors

E. Lindhoff-Last

¹Med. Klinik III, Schwerpunkt Angiologie/Hämostaseologie, Klinikum der J. W. Goethe- Universität Frankfurt am Main
B. Luxembourg

¹Med. Klinik III, Schwerpunkt Angiologie/Hämostaseologie, Klinikum der J. W. Goethe- Universität Frankfurt am Main
I. Pabinger

²Med. Klinik I, Abteilung für Hämatologie und Hämostaseologie, Wien

Abstract

Zusammenfassung

Es wird ein Überblick über Definitionen, Epidemiologie, Klinik der angeborenen und erworbenen Thrombophilien gegeben, wobei der Fokus auf evidenzbasierten Daten liegt. Selektives Thrombophilie-Screening, das auf einer positiven Eigen- und/oder Familienanamnese beruht, ist wesentlich kosteneffektiver als ein universelles Screening. Bei der Mehrzahl der Patienten mit venösen Thrombosen beeinflussen die Ergebnisse eines Thrombophilie-Screenings nicht die Therapiedauer mit oralen Antikoagulanzien. Die einzige Gruppe, die eindeutig von einem Screening in dieser Situation profitiert, sind Patienten mit einem Anti - phospholipidsyndrom, da bei ihnen durch eine prolongierte Antikoagulation das hohe Rezidivthromboserisiko minimiert werden kann. Da das Thromboserisiko während einer Schwangerschaft und im Wochenbett deutlich erhöht ist, kann ein Screening bei ausgewählten Patientinnen mit venösen Thrombosen in der Vorgeschichte indiziert sein, um daraus ggf. eine Indikation für eine Antikoagulation während der Schwangerschaft und im Wochenbett abzuleiten. Darüber hinaus lassen sich signifikante Assoziationen von thrombophilen Neigungen mit Früh- und Spätaborten nachweisen, wobei unklar bleibt, inwieweit Heparine oder Low-dose-Aspirin als Therapeutika bei betroffenen Frauen in einer nachfolgenden Schwangerschaft eingesetzt werden sollen, da multizentrische, placebokontrollierte Studien für diese Indikationen noch ausstehen.

Summary

A survey on definitions, epidemiology, clinical manifestations of congenital and acquired thrombophilias is given with focus on evidence-based data. Diagnostic and therapeutical strategies are presented. Selective thrombophilia screening based on previous personal and/or family history of venous thromboembolism is more cost-effective than universal screening in all patient groups. In the majority of patients with venous thrombosis the results of thrombophilia screening do not influence the duration of oral anticoagulation. The only patient population who clearly profits from thrombophilia screening in this situation are patients with a newly diagnosed antiphospholipid syndrome, because prolonged anticoagulation can avoid the high incidence of recurrence in this patient population. Because of the increased risk of venous thrombosis during pregnancy and the puerperium, thrombophilia screening is indicated in selected patients with a previous history of venous thrombosis to be able to decide whether anticoagulation is necessary when these patients become pregnant. Significant associations with early and late pregnancy loss are observed for patients with thrombophilia while it remains unknown whether these patients profit from anticoagulation with heparin or low dose aspirin during their next pregnancy since placebo-controlled multicenter trials are not yet available.

Schlüsselwörter

Thrombophilie - venöse Thrombose - Antithrombinmangel - Protein-C-Mangel - Protein-S-Mangel - Faktor-V-Leiden - Prothrombinvariation - Lupusantikoagulans

Keywords

Thrombophilia - venous thrombosis - antithrombin deficiency - protein C deficiency - protein S deficiency - factor V Leiden - prothrombin variation - lupus anticoagulant

Full Text

References

Literatur
1 Aadland E, Odegaard OR, Roseth A, Try K. Free protein S deficiency in patients with Crohn’s disease. Scand J Gastroenterol 1994; 29: 333-335.
2 Adachi T. Protein S and congenital protein S deficiency: The most frequent congenital thrombophilia in Japanese. Current Drug Targets 2005; 6: 585-592.
3 Aiach M, Borgel D, Gaussem P. et al. Protein C and protein S deficiencies. Semin Hematol 1997; 34: 205-216.
4 Allaart CF, Poort SR, Rosendaal FR. et al. Increased risk of venous thrombosis in carriers of hereditary protein C deficiency defect. Lancet 1993; 341: 134-138.
5 Aparicio C, Dahlbäck B. Molecular mechanisms of activated protein C resistance. Properties of factor V isolated from an individual with homozygosity for the Arg506 to Gln mutation in the factor V gene. Biochem J 1996; 313: 467-472.
6 Arruda VR, Annichino-Bizzacchi JM, Gonclaves MS, Costa FF. Prevalence of the prothrombin gene variant (nt20210) in venous thrombosis and arterial disease. Thromb Haemost 1997; 78: 1430-1433.
7 Balim Z, Kosova B, Falzon K. et al. Budd-Chiari syndrome in a patient heterozygous for the point mutation C20221T of the prothrombin gene. J Thromb Haemost 2003; 1: 852-853.
8 Baglin T, Luddington R, Brown K. et al. Incidence of recurrent venous thromboembolism in relation to clinical and thrombophilic risk factors: prospective cohort study. Lancet 2003; 362: 523-526.
9 Barcat D, Vergnes C, Constans J. et al. When to measure factors VIII:C and XI after an acute venous thromboembolic event?. J Thromb Haemost 2006; 4: 1631-1632.
10 Baroni M, Mazzola G, Kaabache T. et al. Molecular bases of type II protein S deficiency: the I203-D204 deletion in the EGF4 domain alters GLA domain function. J Thromb Haemost 2006; 4: 186-191.
11 Berger M, Moscatelli H, Kulle B. et al. Association of ADAMDECI haplotype with high factor VIII levels in venous thromboembolism. Thromb Haemost 2008; 99: 905-908.
12 Bernardi F, Faioni EM, 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.
13 Bertina RM, Koeleman BP, Koster T. et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-67.
14 Bertina RM. Elevated clotting factor levels and venous thrombosis. Pathophysiol Haemost Thromb 2003; /2004 33: 395-400.
15 Biguzzi E, Razzari C, Lane DA. et al. Molecular diversità and thrombotic risk in protein S deficiency: The PROSIT Study. Hum Mutat 2005; 25: 259-269.
16 Bovill EG, Bauer KA, Dickermann JD. et al. The clinical spectrum of heterozygous protein C deficiency in a large New England kindred. Blood 1989; 73: 712-717.
17 Branch DW, Silver RM, Blackwell JL. et al. Out - come of treated pregnancies in women with antiphospholipid syndrome: an pudate of the Utah experience. Obstet Gynecol 1992; 80: 614-620.
18 Branson HE, Katz J, Marble R. et al. Inherited protein C deficiency and coumarin-responsive chronic relapsing purpura fulminans in a newborn infant. Lancet 1983; 2: 1165.
19 Brotmann DJ, Girod JP, Posch A. et al. Effects of short-term glucocorticoids on hemostatic factors in healthy volunteers. Throm Res 2006; 188: 247-252.
20 Castaman G, Faioni EM, Tosetto A, Bernardi F. The factor V HR2 haplotype and the risk of venous thrombosis: a meta-analysis. Haematologica 2003; 88: 1182-1189.
21 Canonico M, Oger E, Plu-Bureau G. et al. Estrogen and Thromboembolism Risk (ESTHER) Study Group. Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: the ESTHER study. Circulation 2007; 115: 840-845.
22 Ceelie H, Spaargaren-van Riel CC, Bertina RM, Vos HL. G20210A is a functional mutation in the prothrombin gene; effect on protein levels and 3‘-end formation. J Thromb Haemost 2004; 2: 119-127.
23 Ceriello A, Giugliano D, Quatraro A. et al. Possible role for increased C4b-binding protein level in acquired protein S deficiency in type I diabetes. Diabetes 1990; 39: 447-449.
24 Chan WP, Lee CK, Kwong YL. et al. A novel mutation of Arg306 of factor V gene in Hong Kong Chinese. Blood 1998; 91: 1335-1339.
25 Chinthammitr Y, Vos HL, Rosendaal FR, Doggen CJ. The association of prothrombin A19911G polymorphism with plasma prothrombin acitivity and venous thrombosis: Results of the MEGA study, a large population-based case-control study. J Thromb Haemost 2006; 4: 2587-2592.
26 Christiansen SC, Cannegieter SC, Koster T. et al. Thrombophilia, clinical factors and recurrent venous thrombotic events. JAMA 2005; 293: 2352-2361.
27 Clark P, Walker ID. The phenomenon known as acquired activated protein C resistance. Br J Haematol 2001; 115: 767-773.
28 Corral J, Hernandez-Espinosa D, Soria JM. et al. Antithrombin Cambridge II (A384S): an underestimated genetic risk factor for venous thrombosis. Blood 2007; 109: 4258-4263.
29 Couturaud F, Duchemin J, Leroyer C. et al. Groupe d‘Etude de la Thrombose de Bretagne Occidentale (G. E. T. B. O). Thrombin generation in first-degree relatives of patients with venous thromboembolism who have factor V Leiden. A pilot study. Thromb Haemost 2008; 99: 223-228.
30 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 Sci USA 1993; 90: 1004-1008.
31 Danckwardt S, Hartmann K, Katz B. et al. The prothrombin 20209 C→T mutation in Jewich-Moroccan Caucasians: molecular analysis of gain-offuntion of 3‘end processing. J Thromb Haemost 2006; 4: 1078-1085.
32 Danckwardt S, Hartmann K, Katz B. et al. More on: functional analysis of two prothrombin 3’UTR variants: the C20209T variant, mainly found among African-Americans, and the C20209A variant. J Thromb Haemost 2006; 4: 2288-2289.
33 Dati E, Hafner G, Erbes H. et al. ProC Global: the first functional screening assay for the complete protein C pathway. Clin Chem 1997; 43: 1719-1723.
34 Den Heijer M, Lewington S, Clarke R. Homocysteine, MTHFR and risk of venous thrombosis: a meta-analysis of published epidemiological studies. J Thromb Haemost 2005; 3: 292-299.
35 Dixit A, Kannan M, Mahapatra M. et al. Roles of Protein C, Protein S and antithrombin III in acute leukemia. Am J Hematol 2006; 81: 171-174.
36 Erbe M, Rickerts V, Bauersachs RM, Lindhoff-Last E. Acquired protein C and protein S-deficiency in HIV-infected patients. Clin Appl Thromb Hemost 2003; 9: 325-331.
37 Finazzi G, Caccia R, Barbui T. Different prevalence of thromboembolism in the subtypes of congenital antithrombin III deficiency: review of 404 cases. Thromb Haemost 1987; 58: 1094.
38 Finazzi G, Marchioli R, Brancaccio V. et al. A randomized clinical trial of high-intensity warfarin vs. conventional antithrombotic therapy for the prevention of recurrent thrombosis in patients with the antiphospholipid syndrome (WAPS). J Thromb Haemost 2005; 3: 848-863.
39 Franchini M. Haemostasis and pregnancy. Thromb Haemost 2006; 95: 401-413.
40 Franco RF, Maffei FH, Lourenco D. et al. Factor V Arg306→Thr (factor V Cambridge) and factor V Arg306→Gly mutations in venous thrombotic disease. Br J Haematol 1998; 103: 888-890.
41 Franco RF, Elion J, Tavella MH. et al. The prevalence of factor V Arg306→Thr (factor V Cambridge) and factor V Arg306→Gly mutations in different human populations. Thromb Haemost 1999; 81: 312-313.
42 Frost P, Blom HJ, Milos R. et al. MR: a cacicate genetic risk factor for vascular disease: a common mutation in the methylene tetrahydrofolate reductase. Nat Genet 1995; 10: 111-113.
43 Gandrille S, Borgel D, Sala N. et al. Protein S deficiency: a database of mutations – summary of the first update. Thromb Haemost 2000; 85: 918.
44 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 Genet 2001; 28: 389-392.
45 Gomez K, Laffan MA. Hunting for the mutation in inherited thrombophilia. Blood Coagul Fibrinolysis 2004; 15: 125-127.
46 Goodman CS, Coulam CB, Jeyendran RS. et al. Which thrombophilic gene mutations are risk factors for recurrent pregnancy loss?. Am J Reprod Immunol 2006; 56: 230-236.
47 Griffin JH, Evatt BL, Wideman C, Fernandez JA. Anticoagulant protein C pathway defective in a majority of thrombophilic patients. Blood 1993; 82: 1989-1993.
48 Griffin JH, Evatt BL, Zimmermann TS. et al. Deficiency of protein C in congenital thrombotic disease. J Clin Invest 1981; 68: 1370-1373.
49 Hach-Wunderle V. Die Venenthrombose in der Schwangerschaft. VASA 2003; 32: 61-68.
50 Harper PL, Theakston E, Ahmed J, Ockelford P. D-dimer concentration increases with age reducing the clinical value of the D-dimer assay in the elderly. Intern Med J 2007; 37: 607-613.
51 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 Med 1997; 241: 427-433.
52 Heeb MJ, Kojima Y, Greengard JS, Griffin JH. Activated protein C resistance: molecular mechanisms based on studies using purified Gln506-factor V. Blood 1995; 85: 3405-3411.
53 Hefler L, Jirecek S, Heim K. et al. Genetic polymorphisms associated with thrombophilia and vascular disease in women with unexplained late intrauterine fetal death: a multicenter study. J Soc Gynecol Investig 2004; 11: 42-44.
54 Herrington DM, Vittinghoff E, Howard TD. et al. Factor V Leiden, hormone replacement therapy, and risk of venous thromboembolic events in women with coronary disease. Arterioscler Thromb Vasc Biol 2002; 22: 1012-1017.
55 Himmelreich G, Rosch R, Neuhaus P, Riess H. Protein S in end stage liver disease and in the course of liver transplantation. Thromb Res 1994; 73: 269-277.
56 Hirsch DR, Mikkola KM, Marks PW. et al. Pulmonary embolism and deep venous thrombosis during pregnancy or oral contraceptive use: prevalence of factor V Leiden. Am Heart J 1996; 131: 1145-1148.
57 Hulstein JJ, Lenting PJ, de Laat B. et al. ®2-Glycoprotein I inhibits von Willebrand factor-dependent platelet adhesion and aggregation. Blood 2007; 110: 1483-1491.
58 Kamphuisen PW, Eikenboom JC, Vos HL. et al. Increased levels of factor VIII and fibrinogen in patients with venous thrombosis are not caused by acute phase reaction. Thromb Haemost 1999; 81: 680-683.
59 Kamphuisen PW, Lensen R, Houwing-Duistermaat J. et al. Heritability of elevated factor VIII antigen levels in factor V Leiden families with thrombophilia. Br J Haematol 2000; 109: 519-522.
60 Kamphuisen PW, Eikenboom JC, Bertina RM. Elevated factor VIII levels and the risk of thrombosis. Arterioscler Thromb Vasc Biol 2001; 21: 731-738.
61 Kaufmann JE, Vischer UM. Cellular mechanisms of the hemostatic effects of desmopressin (DDAVP). J Thromb Haemost 2003; 1: 682-689.
62 Koutroubakis IE, Sfiridaki A, Mouzas IA. et al. Resistance to activated protein C and low levels of free protein S in Greek patients with inflammatory bowel disease. Am J Gastroenterol 2000; 95: 190-194.
63 Koster T, Rosendaal FR, Briet E. et al. Protein C deficiency in a controlled series of unselected outpatients: an infrequent but clear risk for venous thrombosis (Leiden thrombophilia study). Blood 1995; 85: 2756-2761.
64 Koster T, Blann AD, Briet E. et al. Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis. Lancet 1995; 345: 152-155.
65 Kraaijenhagen RA, in’t Anker PS, Koopman MM. et al. High plasma concentration of factor VIIIc is a major risk factor for venous thromboembolism. Thromb Haemost 2000; 83: 5-9.
66 Kraus M, Noah M, Fickenscher K. The PCAT – a simple screening assay for assessing the functionality of the protein C anticoagulant pathway. Thromb Res 1995; 79: 217-222.
67 Kuhle S, Lane DA, Jochmanns K. et al. Homozygous antithrombin deficiency type II (99 Leu to Phe mutation) and childhood thromboembolism. Thromb Haemost 2001; 86: 1007-1011.
68 Kuismanen K, Levo A, Vahtera E. et al. Genetic background of type I protein C deficiency in Finland. Thromb Res 2006; 118: 603-609.
69 Kutteh WH, Triplett DA. Thrombophilias and recurrent pregnancy loss. Semin Reprod Med 2006; 24: 54-65.
70 Lane DA, Bayston T, Olds RJ. et al. Antithrombin mutation database: 2nd 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: 197-211.
71 Lee J, Kim S, Sung Kim J. Sagittal sinus thrombosis associated with transient free protein S deficiency after L-asparaginase treatment: case report and review of the literature. Clin Neurol Neurosurg 2000; 102: 33-36.
72 Lindhoff-Last E, Humpich M, Schmitt J. et al. MIXCON-LA: a precise, sensitive and specific aPTT-based assay for detection of lupus anticoagulant. Clin Appl Thromb Hemost 2002; 8: 163-167.
73 Lindhoff-Last E. When is the D-dimer test after surgery useful?. Dtsch Med Wochenschr 2004; 23 129: 972.
74 Lindhoff-Last E, Luxembourg B. Evidence-based indications for thrombophilia-screening. VASA 2008; 1: 19-30.
75 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: 1935-1941.
76 Martinelli I, Manucci PM, De Stefano V. et al. Different risks of thrombosis in four coagulation defects associated with inherited thrombophilie: a study of 150 families. Blood 1998; 92: 2353-2358.
77 Martinelli I, Battaglioli T, Tosetto A. et al. Prothrombin A19911G polymorphism and the risk of venous thromboembolism. J Thromb Haemost 2006; 4: 2582-2586.
78 Melichart M, Kyrle PA, Eichinger S. et al. Thrombotic tendency in 75 symptomatic, unrelated patients with APC resistance. Wien Klin Wochenschr 1996; 108: 607-610.
79 Merriman L, Greaves M. Testing for thrombophilia: an evidence-based approach. Postgrad Med J 2006; 82: 699-704.
80 Miletich J. Thrombophilia as a multigenic disorder. Semin Thromb Hemost 1998; 24: 13-20.
81 Miletich JP, Shermann L, Broze GJ. Absence of thrombosis in subjects with heterozygous protein C deficiency. N Engl J Med 1987; 317: 991-996.
82 Miyakis S, Lockshin MD, Atsumi T. et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006; 4: 295-306.
83 Moores L, Bilello KL, Murin S. Sex and gender issues and venous thromboembolism. Clin Chest Med 2004; 25: 281-297.
84 Mumford A, McVey JH, Morse CV. et al. Factor V I359T: a novel mutation associated with thrombosis and resistance to activated protein C. Br J Haematol 2003; 123: 496-501.
85 Nicolaes GA, Thomassen Mc, Tans G. et al. Effect of activated protein C on thrombin generation and on the thrombin potential in plasma of normal and APC-resistant individuals. Blood Coag Fibrinolysis 1997; 8: 28-38.
86 O’Donnell J, Tuddenham EG, Manning R. et al. High prevalence of elevated factor VIII levels inpatients referred for thrombophilia screening: role of increased synthesis and relationship to the acute phase reaction. Thromb Haemost 1997; 77: 825-828.
87 O’Donnell J, Mumford AD, Manning RA. et al. Elevation of FVIII : C in venous thromboembolism is persistent and independent of the acute phase response. Thromb Haemost 2000; 83: 10-13.
88 Oger E, Lacut K, le Gal G. et al. for the Edith Collaborative Study group. Hyperhomocysteinemia and low B vitamin levels are independently associated with venous thromboembolism: results from the EDITH study: a hospital-based case-control study. J Thromb Haemost 2006; 4: 793-799.
89 Osmanagaoglu MA, Topcuoglu K, Ozeren M, Bozkaya H. Coagulation inhibitors in preeclamptic pregnant women. Arch Gynecol Obstet 2005; 271: 227-230.
90 Palareti G, Cosmi B, Legnani C. et al. PROLONG investigators. D-dimer testing to determine the duration of anticoagulation therapy. N Engl J Med 2006; 355: 1780-1789.
91 Pardanani A, Lasho TL, Hussein K. et al. JAK2V617F mutation screening as part of the hypercoagulable work-up in the absence of splanchnic venous thrombosis or overt myeloproliferative neoplasm: assessment of value in a series of 664 consecutive patients. Mayo Clin Proc 2008; 83: 457-459.
92 Pavlova A, El-Maarri O. Luxembourg et al. Detection of heterozygous large deletions in the antithrombin gene using multiplex polymerase chain reaction and denatured high performance liquid chromatography. Haematologica 2006; 91: 1264-1267.
93 Patrassi GM, Dal Bo Zanon R, Boscaro M. et al. Further studies on the hypercoagulable state of patients with cushing’s syndrome. Thromb Haemost 1985; 54: 518-520.
94 Picard V, Nowak-Göttl U, Biron-Andreani C. et al. Molecular bases of antithrombin deficiency: twenty-two novel mutations in the antithrombin gene. Human Mutat 2006; 27: 600.
95 Picard V, Presot I, Scarabin PY. et al. Antithrombin Cambridge II (A384S): prevalence in patients of the Paris Thrombosis Study (PATHROS). Blood 2007; 110: 2777-2778.
96 Pollak ES, Lam HS, Russell JE. The G20210A mutation does not affect the stability of prothrombin mRNA in vivo. Blood 2002; 100: 359-362.
97 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: 632-637.
98 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.
99 Primignani M, Martinelli I, Bucciarelli P. et al. Risk factors for thrombophilia in extrahepatic portal vein obstruction. Hepatology 2005; 41: 603-608.
100 Rai RS, Regan L, Clifford K. et al. Antiphospholipid antibodies and beta 2 glycoprotein I in 500 women with recurrent miscarriage: results of a comprehensive screening approach. Hum Reprod 1995; 10: 2001-2005.
101 Rees DC, Cox M, Clegg JB. World distribution of factor V Leiden. Lancet 1995; 346: 1133.
102 Reitsma PH, Bernardi F, Doig RG. et al. Protein C deficiency: a database of mutations, 1995 update. Thromb Haemost 1995; 73: 876-889.
103 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 Med 1995; 332: 912-917.
104 Robertson L, Wu O, Langhorne P. et al. for the Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) Study. Thrombophilia in pregnancy: a systematic review. Br J Haematol 2005; 132: 171-196.
105 Robertson L, Wu O, Langhorne P. et al. for the TREATS Study. Thrombophilia in pregnancy: a systematic review. Br J Haematol 2005; 132: 171-196.
106 Rosendaal FR, Koster T, Vandenbroucke JP. et al. High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance). Blood 1995; 85: 1504.
107 Rosendaal FR, Doggen CJ, Zivelin A. et al. Geographic distributation of the 20210 G to A prothrombin variant. Thromb Haemost 1998; 79: 706-708.
108 Scarabin PY, Oger E, Plu-Bureau G. et al. Differential association of oral and transdermal oestrogen- replacement therapy with venous thromboembolism risk. Lancet 2003; 362: 428-432.
109 Schambeck CM, Hinney K, Haubitz I. et al. Familial clustering of high factor VIII levels in patients with venous thromboembolism. Arterioscler Thromb Vasc Biol 2001; 21: 289-292.
110 Schrijver I, Lenzi TJ, Jones CD. et al. Prothrombin gene variants in non-caucasians with fetal loss and intrauterine growth retardation. J Mol Diagn 2003; 5: 250-253.
111 Schroder W, Koesling M, Wulff K. et al. Largescale screening for factor V Leiden mutation in a north-eastern German population. Haemostasis 1996; 26: 233-236.
112 Schulman S, Svenungsson E, Granqvist S. Anticardiolipin antibodies predict early recurrence of thromboembolism and death among patients with venous thromboembolism following anticoagulant therapy. Duration of anticoagulation study group. Am J Med 1998; 104: 332-338.
113 Seligsohn U, Berger A, Abend A. et al. Homozygous protein C deficiency manifested by massive thrombosis in the newborn. N Engl J Med 1984; 310: 559-562.
114 Seligsohn U, Lubetzky A. Genetic susceptibility to venous thrombosis. N Engl J Med 2001; 344: 1222-1231.
115 Shen L, Dahlbäck B. Factor V and protein S as syn ergistic cofactors to activated protein C in degradation of factor VIIIa. J Biol Chem 1994; 269: 18735-18738.
116 Shen L, He X, Dahlbäck B. Synergistic cofactor function of factor V and protein S to activated protein C in the inactivation of the factor VIIIafactor IXa complex. Thromb Haemost 1997; 78: 1030-1036.
117 Simmonds RE, Ireland H, Lane DA. et al. 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: 8-14.
118 Song KS, Park YS, Kim HK. Prevalence of antiprotein S antibodies in patients with systemic lupus erythematosus. Arthritis Rheum 2000; 43: 557-560.
119 Stahl CP, Wideman CS, Spira TJ. et al. Protein S deficiency in men with long-term human immunodeficiency virus infection. Blood 1993; 81: 1801-1807.
120 Sugiura M. Pregnancy and delivery in protein C deficiency. Current Drug Targets 2005; 6: 577-583.
121 Svensson PJ, Dahlbäck B. Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med 1994; 330: 517-521.
122 Tabernero MD, Tomas JF, Alberca I. et al. Incidence and clinical characteristics of hereditary disorders associated with venous thrombosis. Am J Hematol 1991; 36: 249-254.
123 Tait RC, Walker ID, Perry DJ. et al. Prevalence of antithrombin deficiency in the healthy population. Br J Haematol 1994; 87: 106-112.
124 Tans G, Curvers J, Middeldorp S. et al. A randomized cross-over study on the effects of levonor - gestrel- and desogestrel-containing oral contraceptives on the anticoagulant pathways. Thromb Haemost 2000; 84: 15-21.
125 Tirado I, Mateo J, Soria JM. et al. The ABO blood group genotype and factor VIII levels as independent risk factors for venous thromboembolism. Thromb Haemost 2005; 93: 468-474.
126 Vandenbroucke JP, Rosing J, Bloemenkamp KWM. et al. Oral contraceptives and the risk of venous thrombosis. N Engl J Med 2001; 344: 1527-1535.
127 Varadi K, Rosing J, Tans G. et al. Factor V enhances the cofactor function of protein S in the APCmediated inactivation of factor VIII: influence of the factor VR506Q mutation. Thromb Haemost 1996; 76: 208-214.
128 Vigano-D’Angelo S, D’Angelo A, Kaufman CE. et al. Protein S deficiency occurs in the nephrotic syndrome. Ann Intern Med 1987; 107: 42-47.
129 Vormittag R, Bencur P, Ay C. et al. Low-density lipoprotein receptor-related protein 1 polymorphism 663 C > T affects clotting factor VIII activity and increases the risk of venous thromboembolism. J Thromb Haemost 2007; 5: 497-502.
130 Walker ID. Thrombophilia in pregnancy. J Clin Pathol 2000; 53: 573-580.
131 Willeke A, Gerdsen F, Bauersachs RM, Lindhoff-Last E. Rationelle Thrombophiliediagnostik. Deutsches Ärzteblatt 2002; 99: 2111-2118.
132 Williamson D, Brown K, Luddington R. et al. Factor V Cambridge: a new mutation (Arg306→Thr) associated with resistance to activated protein C. Blood 1998; 91: 1140-1144.
133 Wu O, Robertson L, Twaddle S. et al. for the Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) Study. Screening for thrombophilia in high-risk situations: a meta-analysis and cost-effectiveness analysis. Br J Haematol 2005; 131: 80-90.
134 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.
135 Wylenzek M, Geisen C, Staphenhorst L. et al. A novel point mutation in the 3‘region of the prothrombin gene at position 20221 in a Lebanese/ Syrian family. Thromb Haemost 2001; 85: 943-944.
136 Zöller B, Garcia de Frutos P, Hillarp A, Dahlbäck B. Thrombophilia as a multigenic disease. Haematologica 1999; 84: 59-70.