Uncertain thrombophilia markers

Massimo Franchini; Ida Martinelli; Pier Mannuccio Mannucci

doi:10.1160/TH15-06-0478

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2016; 115(01): 25-30
DOI: 10.1160/TH15-06-0478

Review Article

Schattauer GmbH Schattauer

Uncertain thrombophilia markers

Massimo Franchini

¹Department of Transfusion Medicine and Hematology, Carlo Poma Hospital, Mantova, Italy

,

Ida Martinelli

²Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy

,

Pier Mannuccio Mannucci

³Scientific Direction, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy

› Author Affiliations

Abstract

Summary

The development of venous thromboembolism (VTE), which includes deep-vein thrombosis and pulmonary embolism, may be associated with inherited or acquired risk factors that can be measured in plasma or DNA testing. The main inherited thrombophilias include the plasma deficiencies of the natural anticoagulants antithrombin, protein C and S; the gain-of-function mutations factor V Leiden and prothrombin G20210A; some dysfibrinogenaemias and high plasma levels of coagulation factor VIII. Besides these established biomarkers, which usually represent the first-level laboratory tests for thrombophilia screening, a number of additional abnormalities have been less consistently associated with an increased VTE risk. These uncertain causes of thrombophilias will be discussed in this narrative review, focusing on their clinical impact and the underlying pathogenetic mechanisms. Currently, there is insufficient ground to recommend their inclusion within the framework of conventional thrombophilia testing.

Keywords

Thrombophilia - venous thromboembolism - thrombophilia markers

Full Text

References

References
1 Martinelli I. et al. Thrombotic risk factors: basic pathophysiology. Crit Care Med 2010; 38 (Suppl. 02) S3-S9.
2 Previtali E. et al. Risk factors for venous and arterial thrombosis. Bloood Transfus 2011; 09: 120-138.
3 Martinelli I. et al. Inherited risk factors for venous thromboembolism. Nat Rev Cardiol 2014; 11: 140-156.
4 Franchini M. et al. Inherited thrombophilia. Crit Rev Clin Lab Sci 2006; 43: 249-290.
5 Virchow R. Phlogose und Thrombose im Gefäßsystem; Gesammelte Abhandlungen zur Wissenschaftlichen Medizin. Frankfurt: Staatsdruckerei; 1856
6 Rosendaal FR, Reitsma PH. Genetics of venous thrombosis. J Thromb Haemost 2009; 07 (Suppl. 01) 301-304.
7 Wu O. et al. ABO(H) blood groups and vascular disease: a systematic review and meta-analysis. J Thromb Haemost 2008; 06: 62-69.
8 Franchini M, Mannucci PM. ABO blood group and thrombotic vascular disease. Thromb Haemost 2014; 112: 1103-1109.
9 Mannucci PM, Franchini M. Classic thrombophilic gene variants. Thromb Haemost 2015; 114: 885-889.
10 Kwaan HC, Nabhan C. Hereditary and acquired defects in the fibrinolytic system associated with thrombosis. Hematol Oncol Clin N Am 2003; 17: 103-114.
11 Schuster V. et al. Plasminogen deficiency. J Thromb Haemost 2007; 05: 2315-2322.
12 Gils A, Declerck PJ. The structural basis for the pathophysiological relevance of PAI-1 in cardiovascular diseases and the development of potential PAI-1 inhibitors. Thromb Haemost 2004; 91: 425-437.
13 Dawson SJ. et al. The two allele sequences of a common polymorphism in the promoter of the plasminogen activator inhibitor 1 (PAI–1) gene respond differently to interleukin–1 in HepG2 cells. J Biol Chem 1993; 268: 10739-10745.
14 Francis CW. Plasminogen activator inhibitor-1 levels and polymorphisms. Arch Pathol Lab Med 2002; 126: 1401-1404.
15 Tsantes AE. et al. Association between the plasminogen activator inhibitor–1 4G/5G polymorphism and venous thrombosis. A meta-analysis. Thromb Haemost 2007; 97: 907-913.
16 Ridker PM. et al. Arterial and venous thrombosis is not associated with the 4G/5G polymorphism in the promoter of the plasminogen activator inhibitor gene in a large cohort of US men. Circulation 1997; 95: 59-62.
17 Crowther MA. et al. Fibrinolytic variables in patients with recurrent venous thrombosis: a prospective cohort study. Thromb Haemost 2001; 85: 390-394.
18 Foley JH. et al. Insights into thrombin activatable fibrinolysis inhibitor function and regulation. J Thromb Haemost 2013; 11 (Suppl. 01) 306-315.
19 Monasterio J. et al. Plasma thrombin-activatable fibrinolytic inhibitor (TAFI) among healthy subjects and patients with vascular diseases: a validation study. Pathophysiol Haemost Thromb 2003– 2004; 33: 382-386.
20 van Tilburg NH. et al. Thrombin activatable fibrinolysis inhibitor and the risk for deep vein thrombosis. Blood 2000; 95: 2855-2859.
21 Libourel EJ. 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: 1068-1073.
22 Gohil R. et al. The genetics of venous thromboembolism. A meta-analysis involving approximately 120,000 cases and 180,000 controls. Thromb Haemost 2009; 102: 360-370.
23 Cushman M. et al. Associations of the beta-fibrinogen Hae III and factor XIII Val34Leu gene variants with venous thrombosis. Thromb Res 2007; 121: 339-345.
24 Bagoly Z. et al. Factor XIII clot structure, thrombosis. Thromb Res 2012; 129: 382-387.
25 Lippi G, Guidi G. Lipoprotein(a): an emerging cardiovascular risk factor. Crit Rev Clin Lab Sci 2003; 40: 1-42.
26 Durrington PN. et al. Lipoprotein (a): gene genie. Curr Opin Lipidol 2014; 25: 289-296.
27 Lippi G. et al. Lipoprotein(a) concentration is not associated with venous thromboembolism in a case control study. Haematologica 1999; 84: 726-729.
28 Marcucci R. et al. Increased plasma levels of lipoprotein(a) and the risk of idiopathic and recurrent venous thromboembolism. Am J Med 2003; 115: 601-605.
29 Danik JS. et al. Lipoprotein(a), polymorphisms in the LPA gene, and incident venous thromboembolism among 21483 women. J Thromb Haemost 2013; 11: 205-208.
30 Sofi F. et al. Lipoprotein (a) and venous thromboembolism in adults: a meta-analysis. Am J Med 2007; 120: 728-733.
31 Helgadottir A. 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: 722-729.
32 Eldibany MM, Caprini JA. Hyperhomocysteinaemia and thrombosis: an overview. Arch Pathol Lab Med 2007; 131: 872-884.
33 D’Angelo A, Selhub J. Homocysteine and thtombotic disease. Blood 1997; 90: 1-11.
34 Ray JG. Meta-analysis of hyperhomocysteinaemia as a risk factor for venous thromboembolic disease. Arch Intern Med 1998; 158: 2101-2106.
35 Kluijtmans LA. et al. Molecular genetic analysis in mild hyperhomocysteinaemia: a common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease. Am J Hum Genet 1996; 58: 35-41.
36 Arruda VR. et al. The mutation Ala677 in the methylene tetrahydrofolate reductase gene: a risk factor for arterial disease and venous thrombosis. Thromb Haemost 1997; 77: 818-821.
37 Anderson JL. et al. A mutation in the methylenetetrahydrofolate reductase gene is not associated with increased risk for coronary artery disease or myocardial infarction. J Am Coll Cardiol 1997; 30: 1206-1211.
38 Brattstrom L. et al. Common methylenetetrahydrofolate reductase gene mutation leads to hyperhomocysteinaemia but not to vascular disease: the result of a meta-analysis. Circulation 1998; 98: 2520-2526.
39 Frederiksen J. et al. Methylenetetrahydrofolate reductase polymorphism (C677T), hyperhomocysteinaemia, and risk of ischemic cardiovascular disease and venous thromboembolism: prospective and case-control studies from the Copenhagen City Heart Study. Blood 2004; 104: 3046-3051.
40 Bezemer ID. et al. No association between the common MTHFR 677C-T polymorphism and venous thrombosis. Results from the MEGA Study. Arch Intern Med 2007; 167: 497-501.
41 Simone B. et al. Risk of venous thromboembolism associated with single and combined effects of Factor V Leiden, Prothrombin 20210A and Methylenetethraydrofolate reductase C677T: a meta-analysis involving over 11,000 cases and 21,000 controls. Eur J Epidemiol 2013; 28: 621-647.
42 Mrad M. et al. Association of methylenetetrahydrofolate reductase (A1298C and C677T) polymorphisms with retinal vein occlusion in Tunisian patients. Transfus Apher Sci 2014; 50: 283-287.
43 Domagala TB. et al. Mutations C677T and A1298C of the 5,10-methylenetetrahydrofolate reductase gene and fasting plasma homocysteine levels are not associated with the increased risk of venous thromboembolic disease. Blood Coagul Fibrinolysis 2002; 13: 423-431.
44 Fekih-Mrissa N. et al. Role of methylenetetrahydrofolate reductase A1298C polymorphism in cerebral venous thrombosis. Blood Coagul Fibrinolysis 2013; 24: 118-119.
45 Crawley JT, Lane DA. The haemostatic role of tissue factor pathway inhibitor. Arterioscler Thromb Vasc Biol 2008; 28: 233-242.
46 Ariens RAS. et al. Low levels of heparin-releasable tissue factor pathway inhibitor in young patients with thrombosis. Thromb Haemost 1999; 81: 203-207.
47 Dahm A. et al. Low levels of tissue factor pathway inhibitor (TFPI) increase the risk of venous thrombosis. Blood 2003; 101: 4387-4392.
48 Hoke M. et al. Tissue factor pathway inhibitor and the risk of recurrent venous thromboembolism. Thromb Haemost 2005; 94: 787-790.
49 Zakai NA. et al. Total tissue factor pathway inhibitor and venous thrombosis: the Longitudinal Investigation of Thromboembolism Etiology. Thromb Haemost 2010; 104: 207-212.
50 Kleesiek K. et al. The 536C-->T transition in the human tissue factor pathway inhibitor (TFPI) gene is statistically associated with a higher risk for venous thrombosis. Thromb Haemost 1999; 82: 1-5.
51 Paciaroni K. et al. Prevalence of the C536T mutation in the tissue factor pathway inhibitor (TFPI) gene among patients with venous thromboembolic disease. Thromb Haemost 2001; 85: 938-939.
52 Gonzalez-Conejero R. et al. The TFPI 536C-->T mutation is not associated with increased risk for venous or arterial thrombosis. Thromb Haemost 2000; 83: 787-788.
53 Hessner MJ, Luhm RA. The C536T transition in the tissue factor pathway inhibitor (TFPI) gene does not contribute to risk of venous thrombosis among carriers of factor V Leiden. Thromb Haemost 2000; 84: 724-725.
54 Kyrle PA. et al. High plasma levels of factor VIII and the risk of recurrent venous thrombembolism. N Engl J Med 2000; 343: 457-462.
55 Rosendaal FR. High levels of factor VIII and venous thrombosis. Thromb Haemost 2000; 83: 1-2.
56 Kamphuisen PW. et al. Elevated factor VIII levels and the risk of thrombosis. Arterioscler Thromb Vasc Biol 2001; 21: 731-738.
57 Koster T. et al. Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis. Lancet 1995; 345: 152-155.
58 Koster T. et al. Factor VII and fibrinogen levels as risk factors for venous thrombosis. A case–control study of plasma levels and DNA polymorphisms: the Leiden Thrombophilia Study (LETS). Thromb Haemost 1994; 71: 719-722.
59 van Hylckama Vlieg A. et al. High levels of factor IX increase the risk of venous thrombosis. Blood 2000; 95: 3678-3682.
60 Meijers JC. et al. High levels of coagulation factor XI as a risk factor for venous thrombosis. N Engl J Med 2000; 342: 696-701.
61 de Visser MC. et al. Factor X levels, polymorphisms in the promoter region of factor X, and the risk of venous thrombosis. Thromb Haemost 2001; 85: 1011-1017.
62 Kamphuisen PW. et al. Factor V antigen levels and venous thrombosis: risk profile, interaction with factor V leiden, and relation with factor VIII antigen levels. Arterioscler Thromb Vasc Biol 2000; 20: 1382-1386.
63 Serve E. et al. A two adenine insertion polymorphism in the 3’ untranslated region of factor VII gene is associated with peripheral arterial disease but not with venous thrombosis. Results of case-control studies. Thromb Haemost 2007; 98: 733-737.
64 Kamphuisen PW. et al. Increased levels of factor VIII and fibrinogen in patients with venous thrombosis are not caused by acute phase reactions. Thromb Haemost 1999; 81: 680-683.
65 Weltermann A. et al. The risk of recurrent venous thromboembolism among patients with high factor IX levels. J Thromb Haemost 2003; 01: 28-32.
66 Li Y. et al. Genetic variants associated with deep vein thrombosis: the F11 locus. J Thromb Haemost 2009; 07: 1802-1808.
67 El-Galaly TC. et al. Single nucleotide polymorphisms and the risk of venous thrombosis: results from a Danish case-cohort study. Br J Haematol 2013; 160: 838-841.
68 Bezemer ID. et al. Gene variants associated with deep vein thrombosis. J Am Med Assoc 2008; 299: 1306-1314.
69 Bezemer ID. et al. F9 Malmö, factor IX and deep vein thrombosis. Haematologica 2009; 94: 693-699.
70 Simioni P. et al. X-linked thrombophilia with a mutant factor IX (factor IX Padua). N Engl J Med 2009; 361: 1671-1675.
71 Weiler H, Isermann BH. Thrombomodulin. J Thromb Haemost 2003; 01: 1515-1524.
72 Öhlin AK. et al. Thrombomodulin gene variations and thromboembolic disease. Thromb Haemost 1997; 78: 396-400.
73 Ireland H. et al. Thrombomodulin gene mutations associated with myocardial infarction. Circulation 1997; 96: 15-18.
74 Norlund L. et al. A common thrombomodulin amino acid dimorphism is associated with myocardial infarction. Thromb Haemost 1997; 77: 248-251.
75 Doggen CJM. et al. A mutation in the thrombomodulin gene, 127G to A coding for Ala25Thr, and the risk of myocardial infarction in men. Thromb Haemost 1998; 80: 743-748.
76 Le Flem L. et al. Mutations in promoter region of thrombomodulin and venous thromboembolic disease. Arterioscler Thromb Vasc Biol 1999; 19: 1098-1104.
77 Faioni EM. et al. Mutations in the thrombomodulin gene are rare in patients with severe thrombophilia. Br J Haematol 2002; 118: 595-599.
78 Heit JA. et al. Thrombomodulin gene polymorphisms or haplotypes as potential risk factors for venous thromboembolism: a population-based case-control study. J Thromb Haemost 2005; 03: 710-717.
79 Anastasiou G. et al. Thrombomodulin as a regulator of the anticoagulant pathway: implication in the development of thrombosis. Blood Coagul Fibrinolysis 2012; 23: 1-10.
80 Aleksic N. et al. Prospective study of the A455V polymorphism in the thrombomodulin gene, plasma thrombomodulin, and incidence of venous thromboembolism: the LITE Study. J Thromb Haemost 2003; 01: 88-94.
81 Navarro S. et al. Association of the thrombomodulin gene c.1418C>T polymorphism with thrombomodulin levels and with venous thrombosis risk. Arterioscler Thromb Vasc Biol 2013; 33: 1435-1440.
82 Stearns-Kurosawa DJ. et al. The endothelial cell protein C receptor augments protein C activation by the thrombin-thrombomodulin complex. Proc Natl Acad Sci USA 1996; 93: 10212-10216.
83 Kurosawa S. et al. Identification of functional endothelial protein C receptor in human plasma. J Clin Invest 1997; 100: 411-418.
84 Medina P. et al. Polymorphisms in the endothelial protein C receptor gene and thrombophilia. Thromb Haemost 2007; 98: 564-569.
85 Uitte de Willige S. et al. Haplotypes of the EPCR gene, plasma sEPCR levels and the risk of deep venous thrombosis. J Thromb Haemost 2004; 02: 1305-1310.
86 Wu C. et al. Targeted gene sequencing identifies variants in the protein C and endothelial protein C receptor genes in patients with unprovoked venous thromboembolism. Arterioscler Thromb Vasc Biol 2013; 33: 2674-2681.
87 Medina P. et al. Functional analysis of two haplotypes of the human endothelial protein C receptor gene. Arterioscler Thromb Vasc Biol 2014; 34: 684-690.
88 Dennis J. et al. The endothelial protein C receptor (PROCR) Ser219Gly variant and risk of common thrombotic disorders: a HuGE review and meta-analysis of evidence from observational studies. Blood 2012; 119: 2392-2400.
89 Brown NJ, Vaughan DE. Prothrombotic effects of angiotensin. Adv Intern Med 2000; 45: 419-429.
90 Rigat B. et al. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 1990; 86: 1343-1346.
91 Gonzalez Ordonez AJ. et al. Risk of venous thromboembolism associated with the insertion/ deletion polymorphism in the angiotensin-converting enzyme gene. Blood Coagul Fibrinolysis 2000; 11: 485-490.
92 Wells PS. et al. The ACE D/D genotype is protective against the development of idiopathic deep vein thrombosis and pulmonary embolism. Thromb Haemost 2003; 90: 829-834.
93 Buddingh EP. et al. The angiotensin-converting enzyme gene insertion/deletion polymorphism: insufficient evidence for a role in deep venous thrombosis. J Thromb Haemost 2005; 03: 403-404.
94 Ay C. et al. The angiotensin-converting enzyme insertion/deletion polymorphism and serum levels of angiotensin-converting enzyme in venous thromboembolism. Data from a case control study. Thromb Haemost 2007; 98: 777-782.
95 Hsiao FC, Hsu LA. Meta-analysis of association between insertion/deletion polymorphism of the angiotensin I-converting enzyme gene and venous thromboembolism. Clin Appl Thromb Hemost 2011; 17: 51-57.
96 Chae YK. et al. Inhibition of rennin angiotensin axis may be associated with reduced risk of developing venous thromboembolism in patients with athero-sclerotic disease. PLoS one 2014; 09: e87813.
97 Broze Jr GJ. Protein Z dependent regulation of coagulation. Thromb Haemost 2001; 86: 8-13.
98 Vasse M. Protein Z a protein seeking a pathology. Thromb Haemost 2008; 100: 548-556.
99 Bafunno V. et al. The risk of occurrence of venous thrombosis: focus on protein Z. Thromb Res 2011; 128: 508-515.
100 Sofi F. et al. A meta-analysis of potential risks of low levels of protein Z for diseases related to vascular thrombosis. Thromb Haemost 2010; 103: 749-756.
101 Al-Shanqeeti A. et al. Protein Z and protein Z-dependent protease inhibitor. Determinants of levels and risk of venous thrombosis. Thromb Haemost 2005; 93: 411-413.
102 Razzari C. et al. Polymorphisms of the protein Z-dependent protease inhibitor (ZPI) gene and the risk of venous thromboembolism. Thromb Haemost 2006; 95: 909-910.
103 Martinelli I. et al. Low levels of protein Z and the risk of venous thromboembolism. J Thromb Haemost 2005; 03: 2817-2819.
104 Corral J. et al. Protein Z/Z-dependent protease inhibitor (PZ/PZI) anticoagulant system and thrombosis. Br J Haematol 2007; 137: 99-108.
105 Feys HB. et al. ADAMTS-13 activity to antigen ratio in physiological and pathological conditions associated with an increased risk of thrombosis. Br J Haematol 2007; 138: 534-540.
106 Bittar LF. et al. Polymorphisms and mutations in vWF and ADAMTS13 genes and their correlation with plasma levels of FVIII and vWF in patients with deep venous thrombosis. Clin Appl Thromb Hemost 2011; 17: 514-518.
107 Lotta LA. et al. Next-generation sequencing study finds an excess of rare, coding single-nucleotide variants of ADAMTS13 in patients with deep vein thrombosis. J Thromb Haemost 2013; 11: 1228-1239.