Semin Thromb Hemost 2017; 43(06): 614-620
DOI: 10.1055/s-0036-1598002
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Lipoprotein(a) as a Risk Factor for Venous Thromboembolism: A Systematic Review and Meta-analysis of the Literature

Francesco Dentali
1   Department of Clinical Medicine, Insubria University, Varese, Italy
,
Vera Gessi
1   Department of Clinical Medicine, Insubria University, Varese, Italy
,
Rossella Marcucci
2   Department of Experimental and Clinical Medicine, University of Florence, Firenze, Italy
,
Monica Gianni
3   Cardiology Unit, Hospital of Tradate, Tradate, Italy
,
Anna Maria Grandi
1   Department of Clinical Medicine, Insubria University, Varese, Italy
,
Massimo Franchini
4   Department of Hematology and Transfusion Medicine, Carlo Poma Hospital, Mantua, Italy
› Author Affiliations
Further Information

Publication History

Publication Date:
27 March 2017 (online)

Abstract

Elevated plasma levels of lipoprotein(a) (Lp(a)) are associated with increased cardiovascular risk in several clinical studies. However, there is a lack of data supporting a positive association between elevated Lp(a) levels and venous thromboembolism (VTE). Thus, we conducted a systematic review of the literature to better clarify its role as a risk factor for VTE. Medline and the Embase (up to May 2015) electronic databases were used to identify potentially eligible studies. Studies measuring Lp(a) values in adult patients with deep vein thrombosis and/or pulmonary embolism and in a population of patients without a VTE were selected. Studies on patients with major venous thromboembolic events occurring at other unusual site, case reports, and case series were excluded. The odds ratios (ORs) of the association between high values of Lp(a) and VTE and the weighted mean difference (WMD) in Lp(a) levels in cases and in controls were calculated using a random-effect model. Results were presented with 95% confidence interval (CI). Fourteen studies for a total of more than 14,000 patients were finally included in our analysis. Lp(a) was slightly but significantly associated with an increased risk of VTE (OR: 1.56, 95% CI: 1.36, 1.79; 10 studies, 13,541 patients). VTE patients had significantly higher Lp(a) values compared with controls (WMD: 14.46 mg/L, 95% CI: 12.14, 16.78; 4 studies, 470 patients). Lp(a) appeared to be significantly associated with increased risk of VTE. However, Lp(a) levels were only slightly increased in VTE patients compared with controls.

 
  • References

  • 1 Lippi G, Guidi G. Lipoprotein(a): an emerging cardiovascular risk factor. Crit Rev Clin Lab Sci 2003; 40 (01) 1-42
  • 2 Franchini M, Veneri D, Salvagno GL, Manzato F, Lippi G. Inherited thrombophilia. Crit Rev Clin Lab Sci 2006; 43 (03) 249-290
  • 3 Clarke R, Peden JF, Hopewell JC. , et al; PROCARDIS Consortium. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N Engl J Med 2009; 361 (26) 2518-2528
  • 4 Spence JD, Koschinsky M. Mechanisms of lipoprotein(a) pathogenicity: prothrombotic, proatherosclerotic, or both?. Arterioscler Thromb Vasc Biol 2012; 32 (07) 1550-1551
  • 5 Tsimikas S, Hall JL. Lipoprotein(a) as a potential causal genetic risk factor of cardiovascular disease: a rationale for increased efforts to understand its pathophysiology and develop targeted therapies. J Am Coll Cardiol 2012; 60 (08) 716-721
  • 6 Durrington PN, Schofield JD, Siahmansur T, Soran H. Lipoprotein (a): gene genie. Curr Opin Lipidol 2014; 25 (04) 289-296
  • 7 Danesh J, Collins R, Peto R. Lipoprotein(a) and coronary heart disease. Meta-analysis of prospective studies. Circulation 2000; 102 (10) 1082-1085
  • 8 Sofi F, Marcucci R, Abbate R, Gensini GF, Prisco D. Lipoprotein (a) and venous thromboembolism in adults: a meta-analysis. Am J Med 2007; 120 (08) 728-733
  • 9 Helgadottir A, Gretarsdottir S, Thorleifsson G. , et al. Apolipoprotein(a) genetic sequence variants associated with systemic atherosclerosis and coronary atherosclerotic burden but not with venous thromboembolism. J Am Coll Cardiol 2012; 60 (08) 722-729
  • 10 Stroup DF, Berlin JA, Morton SC. , et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 2000; 283 (15) 2008-2012
  • 11 DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986; 7 (03) 177-188
  • 12 Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003; 327 (7414): 557-560
  • 13 Aito S, Abbate R, Marcucci R, Cominelli E. Endogenous risk factors for deep-vein thrombosis in patients with acute spinal cord injuries. Spinal Cord 2007; 45 (09) 627-631
  • 14 Atsumi T, Khamashta MA, Andujar C. , et al. Elevated plasma lipoprotein(a) level and its association with impaired fibrinolysis in patients with antiphospholipid syndrome. J Rheumatol 1998; 25 (01) 69-73
  • 15 Grifoni E, Marcucci R, Ciuti G. , et al. The thrombophilic pattern of different clinical manifestations of venous thromboembolism: a survey of 443 cases of venous thromboembolism. Semin Thromb Hemost 2012; 38 (02) 230-234
  • 16 Kamstrup PR, Tybjærg-Hansen A, Nordestgaard BG. Genetic evidence that lipoprotein(a) associates with atherosclerotic stenosis rather than venous thrombosis. Arterioscler Thromb Vasc Biol 2012; 32 (07) 1732-1741
  • 17 Libourel EJ, Bank I, Meinardi JR. , et al. Co-segregation of thrombophilic disorders in factor V Leiden carriers; the contributions of factor VIII, factor XI, thrombin activatable fibrinolysis inhibitor and lipoprotein(a) to the absolute risk of venous thromboembolism. Haematologica 2002; 87 (10) 1068-1073
  • 18 Marcucci R, Liotta AA, Cellai AP. , et al. Increased plasma levels of lipoprotein(a) and the risk of idiopathic and recurrent venous thromboembolism. Am J Med 2003; 115 (08) 601-605
  • 19 März W, Aygören E, Trommlitz M, Scharrer I, Gross W. Lipoprotein(a): an indicator of risk in thromboembolic disease? [in German]. Klin Wochenschr 1990; 68 (Suppl. 22) 111-112
  • 20 Van Wersch JW. The behaviour of lipoprotein(a) in patients with various diseases. Scand J Clin Lab Invest 1994; 54 (07) 559-562
  • 21 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 (10) 3364-3368
  • 22 Vormittag R, Vukovich T, Stain M, Lehr S, Minar E, Pabinger I. Lipoprotein (a) in patients with spontaneous venous thromboembolism. Thromb Res 2007; 120 (01) 15-20
  • 23 Császár A, Karádi I, Juhász E, Romics L. High lipoprotein(a) levels with predominance of high molecular weight apo(a) isoforms in patients with pulmonary embolism. Eur J Clin Invest 1995; 25 (05) 368-370
  • 24 McColl MD, Sattar N, Ellison J. , et al. Lipoprotein (a), cholesterol and triglycerides in women with venous thromboembolism. Blood Coagul Fibrinolysis 2000; 11 (03) 225-229
  • 25 Ogunyemi D, Cuellar F, Ku W, Arkel Y. Association between inherited thrombophilias, antiphospholipid antibodies, and lipoprotein A levels and venous thromboembolism in pregnancy. Am J Perinatol 2003; 20 (01) 17-24
  • 26 Todorovska E, Blagoevska M, Dimitrovski K, Makarosvka Bojadzieva T, Dukovski R. Lipid and fibrinolytic dysbalance between patients with deep venous thrombosis. Vox Sanguinis 2010 (99, Suppl 1): 438
  • 27 Malaguarnera M, Vacante M, Russo C. , et al. Lipoprotein(a) in cardiovascular diseases. BioMed Res Int 2013; 2013: 650989
  • 28 Hajjar KA, Nachman RL. The role of lipoprotein(a) in atherogenesis and thrombosis. Annu Rev Med 1996; 47: 423-442
  • 29 Lippi G, Bassi A, Brocco G, Manzato F, Marini M, Guidi G. Lipoprotein(a) concentration is not associated with venous thromboembolism in a case control study. Haematologica 1999; 84 (08) 726-729
  • 30 Lippi G, Guidi G. Standardization and clinical management of lipoprotein(a) measurements. Clin Chem Lab Med 1998; 36 (01) 5-16
  • 31 Tsai AW, Cushman M, Rosamond WD, Heckbert SR, Polak JF, Folsom AR. Cardiovascular risk factors and venous thromboembolism incidence: the longitudinal investigation of thromboembolism etiology. Arch Intern Med 2002; 162 (10) 1182-1189
  • 32 Folsom AR, Chamberlain A. Lipoprotein(a) and venous thromboembolism. Am J Med 2008; 121 (02) e17 , author reply e19
  • 33 Rodger MA, Le Gal G, Carrier M. , et al. Serum lipoprotein (a) levels in patients with first unprovoked venous thromboembolism is not associated with subsequent risk of recurrent VTE. Thromb Res 2010; 126 (03) 222-226
  • 34 Lippi G, Franchini M, Targher G. Screening and therapeutic management of lipoprotein(a) excess: review of the epidemiological evidence, guidelines and recommendations. Clin Chim Acta 2011; 412 (11/12) 797-801