Classic thrombophilic gene variants

Pier Mannuccio Mannucci; Massimo Franchini

doi:10.1160/TH15-02-0141

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2015; 114(05): 885-889
DOI: 10.1160/TH15-02-0141

Theme Issue Article

Schattauer GmbH

Classic thrombophilic gene variants

Authors

Pier Mannuccio Mannucci

¹A. Bianchi Bonomi Hemophilia and Thrombosis Center, IRCCS Ca' Granda Maggiore Policlinico Hospital Foundation, Milan, Italy
Massimo Franchini

²Department of Transfusion Medicine and Hematology, Carlo Poma Hospital, Mantova, Italy

Abstract

Summary

Thrombophilia is defined as a condition predisposing to the development of venous thromboembolism (VTE) on the basis of a hypercoagu-lable state. Over the past decades, great advances in the pathogenesis of VTE have been made and nowadays it is well established that a thrombophilic state may be associated with acquired and/or inherited factors. The rare loss-of-function mutations of the genes encoding natural anticoagulant proteins (i. e. protein C, protein S and antithrombin) and the more common gain-of-function polymorphisms factor V Leiden and prothrombin G20210A are the main genetic determinants of thrombophilia. In addition, non-O blood group has been consistently demonstrated to be the most frequent inherited marker of an increased risk of VTE. The mechanism role of these inherited thrombophilia markers will be discussed in this narrative review.

Keywords

Inherited thrombophilia - natural anticoagulants - factor V Leiden - prothrombin mutation - ABO blood group

Full Text

References

References
1 Martinelli I, Bucciarelli P, Mannucci PM. Thrombotic risk factors: basic pathophysiology. Crit Care Med 2010; 38 (Suppl 2) S3-S9.
2 Previtali E, Bucciarelli P, Passamonti SM. et al. Risk factors for venous and arterial thrombosis. Bloood Transfus 2011; 9: 120-138.
3 Martinelli I, De Stefano V, Mannucci PM. Inherited risk factors for venous thromboembolism. Nat Rev Cardiol 2014; 11: 140-156.
4 Virchow R. Phlogose und Thrombose im Gefafisystem; Gesammelte Abhand-lungen zur Wissenschaftlichen Medizin. Frankfurt, Staatsdruckerei. 1856
5 Lippi G, Franchini M, Targher G. Arterial thrombus formation in cardiovascular disease. Nat Rev Cardiol 2011; 8: 502-512.
6 Rosendaal FR, Reitsma PH. Genetics of venous thrombosis. J Thromb Haemost 2009; 7 (Suppl 1) 301-304.
7 Wu O, Bayoumi N, Vickers MA, Clark P. ABO(H) blood groups and vascular disease: a systematic review and meta-analysis. J Thromb Haemost 2008; 6: 62-69.
8 Franchini M, Mannucci PM. ABO blood group and thrombotic vascular disease. Thromb Haemost 2014; 112: 1103-1109.
9 Mammen EF. Antithrombin: its physiological importance and role in DIC. Semin. Thromb Haemost 1998; 24: 19-25.
10 Roemisch J, Gray E, Hoffmann JN. et al. Antithrombin: a new look at the ac-34. tions of a serine protease inhibitor. Blood Coagul Fibrinolysis 2002; 13: 657-670.
11 Lane DA, Kunz G, Olds RJ. et al. Molecular genetics of antithrombin deficiency. 35. Blood Rev 1996; 10: 59-74.
12 Franchini M, Veneri D, Salvagno GL. et al. Inherited thrombophilia. Crit Rev Clin Lab Sci 2006; 43: 249-290.
13 Mammen EF. Clinical relevance of antithrombin deficiencies. Semin. Hematol 1995; 32 (4 Suppl 2) 2-6.
14 Buchanan GS, Rodgers GM, Branch DW. The inherited thrombophilias: genetics, epidemiology, and laboratory evaluation. Best Pract Res Clin Obst Gynecol 2003; 17: 397-411.
15 Wells PS, Blajchman MA, Henderson P. et al. Prevalence of antithrombin deficiency in healthy blood donors: a cross-sectional study. Am J Hematol 1994; 45: 321-324.
16 Tait RC, Walker ID, Perry DJ. et al. Prevalence of antithrombin deficiency in the healthy population. Br J Haematol 1994; 87: 106-112.
17 De Stefano V, Finazzi G, Mannucci PM. Inherited thrombophilia: pathogenesis, clinical syndromes, and management. Blood 1996; 87: 3531-3544.
18 Lane DA, Mannucci PM, Bauer KA. et al. Inherited thrombophilia: part 1. Thromb Haemost 1996; 76: 651-662.
19 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.
20 Kisiel W. Human plasma protein C. Isolation, characterization and mechanism of activation by alpha-thrombin. J Clin Invest 1979; 64: 761-769.
21 Simioni P. The molecular genetics of familial venous thrombosis. Bailliere's Clin Haematol 1999; 12: 479-503.
22 Griffin JH, Evatt B, Zimmerman TS. et al. Deficiency of protein C in congenital thrombotic disease. J Clin Invest 1981; 68: 1370-1373.
23 Reitsma PH, Bernardi F, Doig RG. et al. Protein C deficiency: a database of mutations, 1995 update. On behalf of the Subcommittee on Plasma Coagulation Inhibitors of the Scientific and Standardization Committee of the ISTH. Thromb Haemost 1995; 73: 876-889.
24 Franco RF, Reitsma PH. Genetic risk factors of venous thrombosis. Hum Gen 2001; 109: 369-384.
25 Comp PC, Esmon CT. Recurrent venous thromboembolism in patients with a partial deficiency of protein S. N Engl J Med 1984; 311: 1525-1528.
26 Borgel D, Gandrille S, Aiach M. Protein S deficiency. Thromb Haemost 1997; 78: 351-356.
27 Garcia de Frutos P, Fuentes-Prior P, Hurtado B. et al. Molecular basis of protein S deficiency. Thromb Haemost 2007; 98: 543-556.
28 Lind-Hallden C, Dahlen A, Hillarp A. et al. Small and large PROS1 deletions but no other types of rearrangements detected in patients with protein S deficiency. Thromb Haemost 2012; 108: 94-100.
29 Pintao MC, Garcia AA, Borgel D. et al. Gross deletions/duplications in PROS1 are relatively common in point mutation-negative hereditary protein S deficiency. Hum Genet 2009; 126: 449-456.
30 Johansson AM, Hillarp A, Sall T. et al. Large deletions of the PROS1 gene in a large fraction of mutation-negative patients with protein S deficiency. Thromb Haemost 2005; 94: 951-957.
31 Dahlback 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.
32 Koster T, Rosendaal FR, Bertina RM. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study. Lancet 1993; 342: 1503-1506.
33 Bertina RM, Koeleman BPC, Koster T. et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-67.
34 Voorberg J, Roelse J, Koopman R. et al. Association of idiopathic venous thromboembolism with a single point-mutation at Arg506 of factor V. Lancet 1994; 343: 1535-1536.
35 Norstrøm E, Thorelli E, Dahlbäck B. Functional characterization of recombinant FV Hong Kong and FV Cambridge. Blood 2002; 100: 524-530.
36 Rees DC, Cox M, Clegg JB. World distribution of factor V Leiden. Lancet 1995; 346: 1133-1134.
37 Rosendaal FR, Koster T, Vandenbroucke JP. et al. High risk of thrombosis in patients homozygous for factor V Leiden. Blood 1995; 85: 1504-1508.
38 Cushman M, Tsai AW, White RH. et al. Deep vein thrombosis and pulmonary embolism in two cohorts: The Longitudinal Investigation of Thromboembolism Etiology. Am J Med 2004; 117: 19-25.
39 Poort SR, Rosendaal FR, 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: 3698-3703.
40 Rosendaal FR, Doggen CJ, Zivelin A. et al. Geographic distribution of the 20210 G to A prothrombin variant. Thromb Haemost 1998; 79: 706-708.
41 Storry JR, Olsson ML. The ABO blood group system revisited: a review and update. Immunohematology 2009; 25: 48-59.
42 Yamamoto F, Clausen H, White T. et al. Molecular genetic basis of the histo-blood group ABO system. Nature 1990; 345: 229-233.
43 Yamamoto F, Cid E, Yamamoto M. et al. ABO research in the modern era of genomics. Transfus Med Rev 2012; 26: 103-118.
44 Lowe J. The blood group-specific human glycosyltransferases. Baillieres Clin Haematol 1993; 6: 465-490.
45 Liumbruno GM, Franchini M. Beyond immunohaematology: the role of the ABO blood group in human diseases. Blood Transfus 2013; 11: 491-499.
46 Garratty G. Blood groups and disease: a historical perspective. Transfus Med Rev 2000; 14: 291-301.
47 Anstee DJ. The relationship between blood groups and disease. Blood 2010; 115: 4635-4643.
48 Gill JC, Endres-Brooks J, Bauer PJ. et al. The effect of ABO blood group on the diagnosis of von Willebrand disease. Blood 1987; 69: 1691-1695.
49 Jenkins PV, O'Donnell JS. ABO blood group determines plasma von Willebrand factor levels: a biologic function after all?. Transfusion 2006; 46: 1836-1844.
50 Gallinaro L, Cattini MG, Sztukowska M. et al. A shorter von Willebrand factor survival in O blood group subjects explains how ABO determinants influence plasma von Willebrand factor. Blood 2008; 111: 3540-3545.
51 O'Donnell JS, McKinnon TA, Crawley JT. et al. Bombay phenotype is associated with reduced plasma-VWF levels and an increased susceptibility to ADAMTS13 proteolysis. Blood 2005; 106: 1988-1991.
52 Franchini M, Mannucci PM. ABO blood group and thrombotic vascular disease. Thromb Haemost 2014; 112: 1103-1109.
53 Wu O, Bayoumi N, Vickers MA. et al. ABO(H) blood groups and vascular disease: a systematic review and meta-analysis. J Thromb Haemost 2008; 6: 62-69.
54 Dentali F, Sironi AP, Ageno W. et al. Non-O blood type is the commonest genetic risk factor for VTE: results from a meta-analysis of the literature. Semin Thromb Haemost 2012; 38: 535-548.
55 Dentali F, Franchini M. Recurrent venous thromboembolism: a role for ABO blood group?. Thromb Haemost 2013; 110: 1110-1111.
56 Gandara E, Kovacs MJ, Kahn KR. et al. Non-OO blood type influences the risk of recurrent venous thromboembolism. A cohort study. Thromb Haemost 2013; 110: 1172-1179.
57 Coppola A, Tufano A, Cerbone AM. et al. Inherited thrombophilia: implications for prevention and treatment of venous thromboembolism. Semin Thromb Haemost 2009; 35: 683-694.
58 Franchini M, Lippi G. The intriguing relationship between ABO blood group, cardiovascular disease and cancer. BMC Med 2015; 13: 7.