Der Einfluss thrombophiler Faktoren auf thromboembolische und andere Schwangerschaftskomplikationen

L. Heilmann; F.-G. v Tempelhoff; S. Gerhold; W. Rath

doi:10.1055/s-2001-16821

Zeitschrift für Geburtshilfe und Neonatologie, Inhaltsverzeichnis

Z Geburtshilfe Neonatol 2001; 205(4): 128-136
DOI: 10.1055/s-2001-16821

ÜBERSICHT

Georg Thieme Verlag Stuttgart · New York

Der Einfluss thrombophiler Faktoren auf thromboembolische und andere Schwangerschaftskomplikationen[1]

The influence of thrombophilic factors on the incidence of deep vein thrombosis and pregnancy complicationsL. Heilmann¹ , F.-G. v. Tempelhoff¹ , S. Gerhold¹ , W. Rath²

¹ Abt. Gynäkologie und Geburtshilfe, Stadtkrankenhaus Rüsselsheim
² Klinik für Gynäkologie und Geburtshilfe, Universitätsklinikum der RWTH Aachen

Abstract

Zusammenfassung

Das Thromboserisiko in der Schwangerschaft ist um das 4,2fache erhöht, wobei die lnzidenz zwischen 0,05 und 0,1 % liegt. Angeborene und erworbene thrombophile Faktoren spielen bei ca. 50 % der Schwangeren mit venöser Thrombose eine Rolle und können gleichzeitig mit dem Auftreten wiederholter Spontanaborte, eines intrauterinen Fruchttodes und der frühen schweren Präeklampsie in Verbindung stehen.Zum gegenwärtigen Zeitpunkt gibt es keine generelle Übereinstimmung darüber, alle Schwangeren mit thrombophilen Risiken einer antithrombotisch-medikamentösen Prophylaxe zuzuführen. Auf alle Fälle sollte bei anamnestischen Hinweisen auf eine tiefe Beinvenenthrombose, auf einen wiederholten Spontanabort, auf eine schwere Präeklampsie einschließlich HELLP-Syndrom, bei Patientinnen mit intrauterinem Fruchttod unklarer Ursache und bei schwerer Plazentainsuffizienz eine Untersuchung der thrombophilen Faktoren durchgeführt werden. Als präventive Maßnahmen stehen die niedermolekularen Heparine allein oder in Kombination mit low-dose-Azetylsalizylsäure (ASS, Aspirin®) zur Verfügung.

Pulmonary embolism and/or deep vein thrombosis are a major cause of maternal mortality. In a number of adverse pregnancy outcome including preeclampsia, recurrent spontaneous abortion, restricted fetal growth and fetal death a role for thrombophilia (acquired and hereditable) has been postulated. Monitoring of acquired factors such as antiphospholipid-antibodies and hereditable factors (factor V Leiden, prothrombin mutation) may help predict the occurrence of pregnancy complications.Low molecular weight heparins (LMWH), since their introduction well established during pregnancy, and the rate of adverse fetal outcomes are related to co-morbidity maternal conditions rather than to the treatment itself. The use of LMWH is recommended for all moderate risk and high-risk pregnant patients.

Schlüsselwörter

Schwangerschaft - Thrombophilie - Thrombose - Präeklampsie - wiederholter Abort

Key words

Pregnancy - thrombophilia - deep vein thrombosis - preeclampsia - recurrent abortion

Volltext

Referenzen

Literatur

1 Eingang: 19. 2. 2001
Angenommen nach Revision: 29. 3. 2001

01 Backos M, Chilcott I, Ray R, Reagan L. Pregnancy complications in women with recurrent miscarriage and antiphospholipid antibodies treated with aspirin and heparin. Hum Reprod. 1997;; 12 61
02 Balasch J, Reverater J C, Fabregues F, Tassies D, Rafel M, Crens M, Vanrell J A. First trimester repeated abortion is not associated with activated protein C resistance. Human Reprod. 1997;; 12 1094-1097
03 Bick R L. Recurrent miscarriage syndrome and infertility caused by blood coagulation protein or platelet defects. Haemat/Oncol Clin North America. 2000;; 14 1117-1131
04 Birsdall M, Pattison N, Chamley L. Antiphospholipid antibodies in pregnancy. Aust NZ J Obstet Gynec. 1992;; 32 328
05 Bockarewa M I, Bremme K, Blombäck M. Arg 506-GLn mutation in factor V and risk of thrombosis during pregnancy. Br J Haematol. 1996;; 92 473-478
06 Branch D W, Silver R M, Blackwell J L et al. Outcome of treated pregnancies in women with antiphospholipid syndrome: an update of the Utah experience. Obstet Gynecol. 1992;; 80 614-620
07 Brenner B, Sarig G, Weiner Z, Youmis J, Blumenfeld Z, Lanir N. Thrombophilic polymorphisms are common in women with fetal loss without apparent cause. Thromb Haemostas. 1999;; 82 6-9
08 Christiansen O B. Epidemiological, immunogenetic and immunotherapeutic aspects of unexplained recurrent miscarriage. Thesis, Kobenhaven; 1997:
09 Clark A L, Branch D W, Silver R M, Harris E N, Pierangeli S, Spinnato J A. Pregnancy complicated by the antiphospholipid syndrome: outcomes with intravenous immunoglobulin therapy. Obstet Gynecol. 1999;; 93 437-441
10 Conard J, Horellou M H, van Dreden P, Lecomte T, Samama M. Thrombosis and pregnancy in congenital deficiencies in ATIII, protein C or protein S. Thromb Haemostas. 1990;; 63 319-320
11 Conard J, Horellou M H, van Dreden P, Samama M. Pregnancy and congenital deficiency in antithrombin m or protein C. Thromb Haemostas. 1987;; 58 39
12 Cook G, Walker D, Mc Call F. Familiar thrombophilia and activated protein C resistance - thrombotic risk in pregnancy?. Br J Haematol. 1994;; 87 873-875
13 Cowchock S. Treatment of antiphospholipid syndrome in pregnancy. Lupus. 1998;; 7, Suppl. 2 95-97
14 De Stefano V, Mastrangelo S, Paciaroni K, Ireland M, Lane D A, Scirpa P, Bizzi B, Leone G. Thrombotic risk during pregnancy and puerperium in women with APC resistence - effective subcutaneous heparin prophylaxis in pregnant patients. Thromb Haemostas. 1995;; 74 793-794
15 De Vries J IP, Dekker G A, Huijgens P C. Hyperhomocysteinaemia and protein S deficiency in complicated pregnancies. Br J Obstet Gynaecol. 1997;; 104 1248
16 Deitcher S R, Park V M, Kutteh W H. Prothrombin 20210G > A mutation analysis in Caucasian women with early first trimester pregnancy loss. Blood Suppl. 1998;; 1 92
17 Dekker G A, de Vries J P, Doelitsch P M, Huijens P C, von Blomberg B ME, van Geijn H P. Underlying disorders associated with severe early onset preeclampsia. Am J Obstet Gynecol. 1996;; 173 1042
18 Department of Health, Welsh Office, Scottish Home and Health Department and Department of Health and Social Service Northern Ireland .Confidential Enquiries into maternal death in the. United Kingdom. London; 1998;: 1994-1997
19 DeSwiet M. Thromboembolic disease. In: High risk pregnancy. James DK, Steer PJ, Weiner CP, Ganik B. Saunders WP; 1999:
20 Dilley A, Hopper W, Janil M E, Austin H, Evatt R, Philipp C S. The role of four coagulation genes in thrombosis during pregnancy: Factor V Leiden, Prothrombin 20210, MTHFR, ACE. Thromb Haemostas. 1999;; Suppl 1 227
21 Dizon-Townson D S, Nelson L M, Easton K, Ward K. The factor V Leiden mutation may predispose women to severe preeclampsia. Am J Obstet Gynecol. 1996;; 175 902
22 Foka Z J, Lambropoulos A F, Saravelos H et al. Factor V Leiden and prothrombin 620210A mutations but not methylentetrahydrofolat reductase C677T are associated with recurrent miscarriage. Human Reprod. 2000;; 15 458-462
23 Friederich P W, Samson B J, Simioni P, Zanardi S, Huisman M V, Kindt L, Prandoni P, Büller H R, Girolami A, Prins M H. Frequency of pregnancy related thromboembolism in anticoagulant factor deficient women: Implications for prophylaxis. Ann Int Med. 1996;; 125 955-960
24 Gerhardt A, Scharf R E, Beckmann M W, Struwe S, Bender H G, Pillny N, Sandmann W, Zotz R B. Prothrombin and factor V mutations in women with a history of thrombosis during pregnancy and the puerperium. New Engl J Med. 2000;; 342 374-380
25 Gherman R B, Goodwin T M, Leung B, Byrne J D, Hethumumi R, Montorro M. Incidence, clinical characteristics and timing of objectively diagnosed venous thromboembolism during pregnancy. Obstet Gynec. 1999;; 94 7309-7334
26 Ginsberg J S. Thromboembolism and pregnancy. Thromb Haemostas. 1999;; 82 620
27 Girolami A, Simioni P, Girolami B, Scarano L. G to A 20210 Prothrombin polymorphism and venous thrombosis: simple association or causal relationship?. Clin Appl Thromb/Hemost. 2000;; 6 135-138
28 Grandone E, Margaglione M, Colaizzo D. Factor V Leiden, C > T MTHFR Polymorphismus and genetic susceptibility to preeclampsia. Thromb Haemostas. 1997;; 77 1052
29 Grandone E, Margaglione M, Colaizzo D. Prothrombotic genetic risk factors and the occurrence of gestational hypertension with or without proteinuria. Thromb Haemostas. 1999;; 81 349
30 Grandone E, Margaglione M, Colaizzo D, Andrea G D, Cappucci G, Brancaccio V, di Minno G. Genetic susceptibility to pregnancy related to venous thromboembolism: Roles for factor V Leiden, prothrombin G20210A and methylene tetrahydrofolate reductase C677T mutations. Amer J Obstet Gynec. 1998;; 179 1324-1328
31 Grandone E, Margaglione M, Colaizzo D et al. Faktor V Leiden is associated with repeated and recurrent fetal losses. Thromb Haemost. 1997;; 77 822-824
32 Granger K A, Farquharson R G. Obstetric outcome in antiphospholipid syndrome. Lupus. 1997;; 6 509-513
33 Greaves M. Antiphospholipid antibodies and thrombosis. Lancet. 1999;; 353 1348-1353
34 Greer I A, de Swiet M. Thrombosis prophylaxis in obstetric and gynecology. Br J Obstet Gynecol. 1993;; 100 37
35 Greer I A. Epidemiology, risk factors and prophylaxis of venous thromboembolism in obstetrics and gynecology. Bailliers Clin Obstet Gynecol. 1997;; 11 403-430
36 Greer I A. Thrombosis in pregnancy: malemal and fetal issues. Lancet. 1999;; 353 1258-1265
37 Hallak M, Senderowicz J, Cassel A, Shapira Ch, Agkai E, Auslender R, Abramovici H. Activated protein C resistance (factor V Leiden) associated with thrombosis in pregnancy. Am J Obstet Gynecol. 1997;; 176 889-893
38 Heilmann L, Schneider D M, v Tempelhoff G F, Kuse S. Antiphospholipid-antibodies and other thrombophilic defects in patients with a history of early onset severe preeclampsia or HELLP-syndrome. Geburtsh u Frauenheilk. 1999;; 59 95-100
39 Heilmann L, Schneider D M, von Tempelhoff G F. Antithrombotic therapy in high risk pregnancy. Hemat/Oncol Clin North America. 2000;; 14 1133-1150
40 Heinrich F. Venenthrombosen und Lungenembolien in der Schwangerschaft und im Wochenbett. Med Welt. 2000;; 51 (Suppl 1) 1-32
41 Hellgren M, Svensson P J, Dahlbäck B. Resistance to activated protein C as a basis for venous thromboembolism associated with pregnancy and oral contraceptives. Am J Obstet Gynecol. 1995;; 173 210-213
42 Hellgren M, Tengborn L, Abildgaard U. Pregnancy in women with congenital antithrombin III deficiency: Experience of treatment with heparin and antithrombin. Gynecol Obstet Invest. 1982;; 13 76-89
43 Hirsch D R, Mikkola K M, Marks P W, Fox E A, Dorfman D M, Evenstein B M, Goldhaber S Z. Pulmonary embolism and deep venous thrombosis during pregnancy or oral contraceptive use. Prevalence of factor V Leiden. Am Heart J. 1996;; 131 1145-1148
44 Holmes Z, Packos M, Atoyebi W, Pickering W, Regan L, Cohen H. Screening for heritable thrombophilic risk factors in a recurrent miscarriage population. Thromb Haemostas. 1999;; Suppl 534
45 Katano K, Aoki K, Sasa H, Ogasawara M, Matsuura E, Yagami Y. β2-Glycoprotein I-dependent anticardiolipid antibodies as a predictor of adverse pregnancy outcomes in healthy pregnant women. Human Reproduction. 1996;; 11 509-512
46 Khamashta M A. Management of thrombosis and pregnancy loss in the antiphospholipid syndrome. Lupus. 1998;; 7, Suppl 2 62-65
47 Kornberg A, Raziel A, Rahimini-Levene N, Yono R, Sela B A, Ron-El R. Hypercoagulability and recurrent abortion. Blood. 1998;; 92, Suppl 1 121b
48 Krauss Th, Augustin H G, Osmers R, Meden H, Unterhalt M, Kuhn W. Activated protein C resistance and factor V Leiden in patients with hemolysis, elevated liver enzymes, low platelet syndrome. Obstet Gynecol. 1998;; 92 457
49 Krnic-Barrie S, O'Connor C R, Looney S W et al. A retrospective review of 61 patients with antiphospholipid syndrome. Arch Intern Med. 1997;; 157 2101
50 Kupferminc M J, Eldor A, Steinman N. Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med. 1999;; 340 9
51 Kutteh W H. Antiphospholipid antibody-associated recurrent pregnancy loss: treatment with heparin and low dose aspirin is superior to low dose aspirin alone. Am J Obstet Gynecol. 1996;; 174 1584-1589
52 Kutteh W H, Park V M, Deitcher St R. Hypercoagulable stete mutation analysis in white patients with early first trimester recurrent pregnancy loss. Fert Steril. 1999;; 71 1048-1053
53 Landy H J, Kessler C, Kelly W K, Weingold A B. Obstetric performance in patients with the lupus anticoagulant and/or anticardiolipid antibodies. Am J of Perinatology. 1992;; 9 146-151
54 Laskin C A, Bombardier C, Hannah M E, Mandel F P, Ritchie J WK, Farewell V, Farine D, Spitzer K, Fielding L, Soloninka C A, Yeung M. Prednisone and aspirin in women with autoantibodies and unexplained recurrent fetal loss. N Engl J Med. 1997;; 337 148-153
55 Lima F, Khamashta M A, Buchanan N MM. A study of sixty pregnancies in patients with the antiphospholipid syndrome. Clin Exp Rheum. 1996;; 14 131
56 Lindoff C, Ingemarson I, Martinsson G, Segelmark M, Thysell H, Astedt B. Preeclampsia is associated with reduced response to activated protein C. Am J Obstet Gynecol. 1997;; 176 457
57 Linqvist P. Risk estimation and prediction of preeclampsia, IUGR, and thrombosis in pregnancy. Thesis, Malmö; 1999:
58 Lockshin M D, Druzin M L, Qamar T. Prednison does not prevent recurrent fetal death in women with antiphospholipid antibody. Am J Obstet. 1989;; 160 439-443
59 Lubbe W F, Liggins G C. Lupus anticoagulant and pregnancy. Am J Obstet Gynecol. 1985;; 153 322
60 Lynch A, Marlar R, Muurphy J, Davila G, Santos M, Rutledge J, Emlen W. Antiphospholipid antibodies in predicting adverse pregnancy outcome. Ann Intern Med. 1994;; 120 470-475
61 Macklon N S, Greer I A. Venous thrombembolic diseaese in obstetrics and gynaecology. The Scottish experience. Scot Med J. 1996;; 41 83-86
62 McColl N D, Ramsay J, Tait R, Walker J D, McCall F, Conkie J A, Carty M I, Greer I A. Risk factors for pregnancy associated venous thromboembolism. Thromb Haemostas. 1997;; 78 1183-1188
63 Mello G, Parretti E, Martini E et al. Usefulness of screening for congenital or acquired hemostasis abnormalities in women with previous complicated pregnancies. Hemostasis. 1999;; 29 197-203
64 Metz J, Kloss M, Molley C JO et al. Prevalence of FVL is not increased in women with recurrent miscarriage. Clin Appl Thromb/Hemost. 1997;; 3 137-140
65 Mimuro S, Lahoud R, Beutler L, Trudinger B. Changes of resistance to activated protein C in the course of pregnancy and prevalence of factor V mutation. Aust NZ J Obstet Gynaecol. 1998;; 38 200-204
66 Murphy R P, Donoghue C, Nallen R J et al. Prospective evaluation of the risk conferred by FVL and thermolabile methylenetetrahydrofolate reductase polymorphisms in pregnancy. Arterioscler Thromb Vasc Biol. 2000;; 20 266-270
67 Nenfeld M, Koch H G, Auberger K, Schobess R, Bäumer R, Kaise M, Reinkemeier A, Theilling B, Junker R. The PAI-1 4G/4G genotype is a risk factor for venous thrombosis carriers of the FVG1691A mutation. Ann Hematology. 2000;; 79, Suppl I 33
68 Öhlin A K, Norlund L, Marlar R A. Thrombomodulin gene variations and thromboembolic disease. Thromb Haemostas. 1997;; 78 396
69 Out H J, Bruinse H W, Christiaens G CML, vanVliet M, deGroot P G, Nieuwenhuis H K, Derksen R HWM. A prospective, controlled multicenter study on the obstetric risks of pregnant women with antiphospholipid antibodies. Am J Obstet Gynecol. 1992;; 167 26-32
70 Peltier J Y, de Mazancourt P, Beaufils F, Guyot B, Beumebarek Y, Doleans M, Richard L, de Rancourt E. Incidence of metabolic and hemostatic variables in 72 women with pregnancy induced hypertension. Thromb Haemostas. 1999;; Suppl 534
71 Pickering W, Holmes Z, Regan L, Cohen H. Normal prevalence of the G20210A prothrombin gene mutation in women with recurrent miscarriage. Br J Haematol. 1998;; 102 250
72 Poort S R, Rosedaal F R, Reimtsa 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
73 Preston F E, Rosendaal F R, Walter I D. Increased fetal loss in women with heritable thrombophilia. Lancet. 1996;; 348 913
74 Rai R, Cohen H, Dave M, Regan L. Randomized controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies). BMJ. 1997;; 314 253
75 Rai R, Regan L, Hadley E, Dave M, Kohen H. Second trimester pregnancy loss is associated with activated protein C resistance. Br J Hematol. 1996;; 92 489
76 Rand J H, Wu X X, Guller S. Reduction of annexin V (placental anticoagulant protein I) on placental villi of women with antiphospholipid antibodies and recurrent spontaneous abortion. Am J Obstet Gynecol. 1994;; 171 1566
77 Rath W, Heilmann L. Gerinnungsstörungen in Gynäkologie und Geburtshilfe. Thieme, Stuttgart; 1999:
78 Ray J G, Laskin C A. Folic acid and homocysteine metabolic defects and the risk of placental abruption, preeclampsia and spontaneous pregnancy loss: a systematic review. Placenta. 1999;; 20 519-529
79 Reece E A, Gabrielli S, Cullen M T et al. Recurrent adverse pregnancy outcome and antiphospholipid antibodies. Am J Obstet Gynecol. 1990;; 163 162-169
80 Reece E A, Garofalo J, Zheng X Z, Assimakopoulos E. Influence of antiphospholipid antibody titer, prior pregnancy losses and treatment. J Reprod Med. 1997;; 42 49-55
81 Ridker P M, Miletich J P, Buring J E, Ariya A A, Priel D T, Manson J AK, Hill J A. Factor V Leiden mutation is a risk factor for recurrent pregnancy loss. Ann Int Med. 1998;; 128 1000
82 Rosendaal F R. Risk factors for venous thrombotic disease. Thromb Haemostas. 1999;; 82 610-619
83 Rutherford S E, Montero M, Mc Schee W. Thromboembolic disease associated with pregnancy: An 11 year review. Am J Obstet Gynecol. 1991;; 164 286
84 Sarig G, Hoffimann R, Youmis J, Lanir N, Blumenfeld Z, Brenner B. Thrombophilia is common in women with pregnancy loss associated with late pregnancy wastage. Thromb Haemostas. 1999;; Suppl I 226
85 Silver R N, Draper M J, Scott J R et al. Clinical consequences of antiphospholipid antibodies: An historic cohort study. Obstet Gynecol. 1994;; 83 372
86 Spina V, Alexandri V, Morini F. The impact of the factor V Leiden mutation on pregnancy. Human Reproduction. 2000;; 6 301-306
87 Thorarensen O, Ryan S, Hunter J et al. Factor V Leiden mutation and unrecognized cause of hemiplegic cerebral palsy, neonatal stroke and placental thrombosis. Ann Neurol. 1997;; 42 372-375
88 Triplett D A. Obstetrical complications associated with antiphospholipid antibodies. In: Coulam CB, Faulk WP, McIntyre JA: Immunological Obstetrics. Norton Medical Books; 1992:
89 Valennsise H, Vaquero E, de Carolis C, Stipa E, Perricone R, Arundini D, Romanini C. Normal fetal growth in women with antiphospholipid syndrome treated with high-dose intravenous immunoglobulin (IVIG). Prenatal Diagnosis. 1995;; 15 509-517
90 Vandenbroucke J P, van der Meer F JM, Helmerhorst F M, Rosendaal F R. Factor V Leiden: should we screen oral contraceptive users and pregnant women?. Brit Med J. 1996;; 313 1127-1130
91 Van Pampus M G, Dekker G A, Wolf H. High prevalence of hemostatic abnormalities in women with a history of severe preeclampsia. Am J Obstet Gynecol. 1999;; 180 1146
92 Vincente V, Rodriguez C, Soto I, Fernandez M, Moraleda J M. Risk of thrombosis during pregnancy and postpartum in hereditary thrombophilia. Am J Haematol. 1994;; 46 151
93 Vollset S E, Bjorke-Monsen A AL, Irgens L M. Plasma total homocysteine and previous pregnancies: the Hordaland Homocysteine Study. Proceedings of the 2nd International Symposium on Homocysteine. Neijmegen, Holland; 1998:
94 Walker I D. Thrombophilia in pregnancy. J Clin Pathol. 2000;; 53 573-580
95 Walker M C, Smith G M, Perkins S L. Changes in homocystein levels during normal pregnancy. Am J Obstet Gynecol. 1999;; 180 660
96 Wilson W A, Gharafi A E, Koike T, Lockshin M, Branch D W, Piete J Ch, Brey R, Derksen R, Harris H N, Hughes G RV, Triplett D A, Khamashta M A. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome. Arthr & Rheumat. 1999;; 42 1309-1311
97 Wramsby M, Bremme K, Lindner St, Blombäck M. Prevalence of factor V G1691A mutation and prothrombin 20210A polymorphism in women with habitual abortions. Thromb Haemostas. 1999;; Suppl 541
98 Yasuda M, Takakuwa K, Tokunaga A, Tanaka K. Prospective studies of the association between anticardiolipin antibody and outcome of pregnancy. Obstet Gynecol. 1995;; 86 555-559
99 Younis J S, Brenner B, Okel G et al. Activated protein C resistance and FVL mutation can be associated with first as well as second trimester recurrent pregnancy loss. Am J Reprod. 2000;; 43 31-35

Prof. Dr. med. L. Heilmann

Abteilung Gynäkologie/Geburtshilfe
Stadtkrankenhaus Rüsselsheim

65428 Rüsselsheim