Lipoprotein (a) and other prothrombotic risk factors in Caucasian women with unexplained recurrent miscarriage

Manuela Krause; Barbara Sonntag; Robert Klamroth; Achim Heinecke; Carola Scholz; Claus Langer; Inge Scharrer; Robert R. Greb; Arnold von Eckardstein; Ulrike Nowak-Göttl

doi:10.1160/TH04-08-0519

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2005; 93(05): 867-871
DOI: 10.1160/TH04-08-0519

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Lipoprotein (a) and other prothrombotic risk factors in Caucasian women with unexplained recurrent miscarriage

Results of a multicentre case-control study

Manuela Krause

¹Department of Internal Medicine, Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany

,

Barbara Sonntag

²Departments of Obstetrics and Gynecology, University of Münster, Germany

,

Robert Klamroth

³Department of Internal Medicine, Vivantes Hospital Berlin Friedrichshain, Germany

,

Achim Heinecke

⁴Institute of Medical Informatics and Biomathematics, University of Münster, Germany

,

Carola Scholz

⁵Pediatric Hematology and Oncology, University of Münster, Germany

,

Claus Langer

⁶Institute of Clinical Chemistry and Institute of Arteriosclerosis Research, University of Münster, Germany

,

Inge Scharrer

¹Department of Internal Medicine, Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany

,

Robert R. Greb

²Departments of Obstetrics and Gynecology, University of Münster, Germany

,

Arnold von Eckardstein

⁷Institute of Clinical Chemistry, University of Zürich, Switzerland

,

Ulrike Nowak-Göttl

⁵Pediatric Hematology and Oncology, University of Münster, Germany

› Author Affiliations

Abstract

Summary

From 1998 to 2003, 133 Caucasian women aged 17–40 years (median 29 years) suffering from unexplained recurrent miscarriage (uRM) were consecutively enrolled. In patients and 133 age-matched healthy controls prothrombotic risk factors (factor V (FV) G1691A, factor II (FII) G20210A, MTHFR T677T, 4G/5G plasminogen activator inhibitor (PAI)-1, lipoprotein (Lp) (a), protein C (PC), protein S (PS), antithrombin (AT), antiphospholipid/anticardiolipin (APA/ACA) antibodies) as well as associated environmental conditions (smoking and obesity) were investigated. 70 (52.6%) of the patients had at least one prothrombotic risk factor compared with 26 control women (19.5%; p<0.0001). Body mass index (BMI; p=0.78) and smoking habits (p=0.44) did not differ significantly between the groups investigated. Upon univariate analysis the heterozygous FV mutation, Lp(a) > 30 mg/dL, increased APA/ACA and BMI > 25 kg/m² in combination with a prothrombotic risk factor were found to be significantly associated with uRM. In multivariate analysis, increased Lp(a) (odds ratio (OR): 4.7/95% confidence interval (CI): 2.0–10.7), the FV mutation (OR:3.8/CI:1.4–10.7), and increased APA/ACA (OR: 4.5/CI: 1.1–17.7) had independent associations with uRM.

Keywords

Lipoprotein (a) - recurrent miscarriage

Full Text

References

References
1 De Stefano V, Finazzi G, Mannucci PM. Inherited thrombophilia: pathogenesis, clinical syndromes, and management. Blood 1996; 87: 3531-44.
2 Seligsohn U, Lubetsky A. Genetic susceptibility to venous thrombosis. N Engl J Med 2001; 344: 1222-31.
3 Schaefer EJ, Lamon-Fava S, Jenner JL. et al. Lipoprotein( a) levels and risk of coronary heart disease in men. The lipid Research Clinics Coronary Primary Prevention Trial. JAMA 1994; 271: 999-1003.
4 Nagayama M, Shinohara Y, Nagayama T. Lipoprotein( a) and ischemic cerebrovascular disease in young adults. Stroke 1994; 25: 74-8.
5 Ariyo AA, Thach C, Tracy R. Lp(a) lipoprotein, vascular disease and mortality in the elderly. N Engl J Med 2003; 349: 2108-15.
6 Nowak-Göttl U, Junker R, Hartmeier M. et al. Increased lipoprotein(a) is an important risk factor for venous thromboembolism in childhood. Circulation 1999; 100: 743-8.
7 von Depka M, Nowak-Göttl U, Eisert R. et al. Increased lipoprotein (a) levels as an independent risk factor for venous thromboembolism. Blood 2000; 96: 3364-8.
8 Utermann G. The mysteries of lipoprotein(a). Science 1989; 246: 904-10.
9 Hajjar KA, Gavish D, Breslow JL. et al. Lipoprotein( a)modulationof endothelial cell surface fibrinolysis and its potential role in atherosclerosis. Nature 1989; 339: 303-5.
10 Brenner B, Sari G, Weiner Z. et al. Thrombophilic polymorphisms are common in women with foetal loss without apparent cause. Thromb Haemost 1999; 82: 6-9.
11 Kupferminc MJ, Eldor A, Steinman N. et al. Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med 1999; 340: 9-13.
12 Berg K, Roald B, Sande H. High Lp(a) lipoprotein level in maternal serum may interfere with placental circulationand cause fetal growthretardation. Clin Gen 1994; 46: 52-6.
13 Kutteh WH, Park VM, Deitcher SR. Hypercoagulable state mutation analysis in white patients with early first-trimester recurrent pregnancy loss. Fertil Steril 1999; 71: 1048-53.
14 Martinelli I, Taioli E, Cetin I. et al. Mutations in coagulation factors in women with unexplained late fetal loss. N Engl J Med 2000; 343: 1015-8.
15 Sarig G, Younis JS, Hoffman R. et al. Thrombophilia is common inwomenwith idiopathic pregnancyloss and is associated with late pregnancy wastage. Fertil Steril 2002; 77: 342-7.
16 Hohlagschwandtner M, Unfried G, Heinze G. et al. Combined thrombophilic polymorphisms in women with idiopathic recurrent miscarriage. Fertil Steril 2003; 79: 1141-8.
17 Rey E, Kahn SR, David M. et al. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet 2003; 361: 901-8.
18 Clifford K, Rai R, Watson H. et al. An informative protocol for the investigation of recurrent miscarriage: preliminary experience of 500 consecutive cases. Hum Reprod 1994; 9: 1328-32.
19 Walker MC, Ferguson SE, Allen VM. Heparin for pregnant women with acquired or inherited thrombophilias. Cochrane Database Syst Rev. 2003: CD003580.
20 Stirrat GM. Recurrent spontaneous abortion. Coulam CB, Faulk WP, Mc Intrue JA. eds Immunological Obstetrics New York: W.W. Norton & Company; 1992: 357-76.
21 Bertina RM, Koelemann BPC, Koster T. et al. Mutation in blood coagulation factor V associated with resistance toactivated protein C. Nature 1994; 396: 64-7.
22 Poort SR, Rosendaal F, Reitsma PH. et al. 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.
23 Froost P, Bloom HJ, Milos R. et al. Acandidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995; 10: 111-3.
24 Falk G, Almquist A, Nordenhem A. et al. Allele specific PCR for detection of a sequence polymorphism in the promoter region of the plasminogen activator inhibitor-1 (PAI-1) gene. Fibrinolysis 1995; 9: 170-4.
25 Junker R, Koch HG, Auberger K. et al. Prothrombin G20210A gene mutation and further prothrombotic risk factors in childhood thrombophilia. Arterioscler Thromb Vasc Biol 1999; 19: 2568-72.
26 Hosmer DW, Lemeshow S. Applied logistic regression. New York: Wiley; 1989: pp 187-215.
27 Van Pampus MG, Koopman MM, Wolf H. et al. Lipoprotein (a) concentrations inwomenwitha history of severe preeclampsia. A case-control study. Thromb Haemost 1999; 82: 10-3.
28 Von Kries R, Junker R, Oberle D. et al. Foetal growth restriction in children with prothrombotic risk factors. Thromb Haemost 2001; 86: 1012-6.
29 Von Eckardstein A, Schulte H, Cullen P. et al. Lipoprotein (a) further increases the risk of coronary events in men with high global cardiovascular risk. J Am Col Cardiol 2001; 37: 434-9.
30 Danesh J, Collins R, Peto R. Lipoprotein (a) and coronary heart disease. Meta-analysis of prospective studies. Circulation 2000; 102: 1082-5.
31 Sträter R, Becker S, von Eckardstein A. et al. Prospective assessment of risk factors of recurrent stroke during childhood – a 5-year follow-up study. Lancet 2002; 360: 1540-5.
32 Kronenberg F, Lingenhel A, Lhotta K. et al. The apolipoprotein (a) size polymorphism is associated with nephrotic syndrome. Kidney Int 2004; 65: 606-12.
33 Seriolo B, Accardo S, Fasciolo D. et al. Lipoproteins, anticardiolipin antibodies and thrombotic events in rheumatoid arthritis. Clin Exp Rheumatol 1996; 14: 593-9.
34 Harpel PC, Gordon BR, Parker TS. Plasmin catalyzes binding of lipoprotein (a) to immobilized fibrinogen and fibrin. Proc Natl Acad Sci USA 1989; 86: 3847-51.
35 Scanu AM, Fless GM. Lipoprotein (a). Heterogeneity and biological relevance. J Clin Invest 1990; 85: 1709-15.
36 Hancock MA, Boffa MB, Marcovina SM. et al. Inhibition of plasminogen activation by lipoprotein(a): critical domains in apolipoprotein(a) and mechanism of inhibition on fibrin and degraded fibrin surfaces. J Biol Chem 2003; 287: 23260-9.
37 Utermann G, Duba C, Menzel HJ. Genetics of the quantitative Lp(a) lipoprotein trait. II. Inheritance of Lp(a) glycoprotein phenotypes. Hum Genet 1988; 78: 47-50.
38 Boerwinkle E, Leffert CC, Lin J. et al. Apolipoprotein (a) gene accounts for greater than 90%of the variation in plasma lipoprotein (a) concentrations. J Clin Invest 1992; 90: 52-60.
39 Glueck CJ, Kupferminc MJ, Fontaine RN. et al. Genetic hypofibrinolysis in complicated pregnancies. Obstet Gynecol 2001; 97: 44-8.
40 Gris JC, Mercier E Quere. et al. Low-molecularweight heparin versus low-dose aspirin in women with one fetal loss and a constitutional thrombophilic disorder. Blood 2004; 103: 3695-9.
41 Kovalevsky G, Gracia CR, Berlin JA. et al. Evaluation of the association between hereditary thrombophilias and recurrent pregnancy loss. A meta-analysis. Arch Internal Med 2004; 164: 558-63.