Genetics in thrombophilia

Summary

Venous thromboembolism (VTE) poses a worldwide health burden affecting millions of people each year. The annual incidence of symptomatic VTE, the collective term used here for deep venous thrombosis, pulmonary embolism or both, is 2–3 per thousand inhabitants. The one-year mortality is 20% after a first VTE. Of the surviving patients 15–25% will experience a recurrent episode of VTE in the three years after the first event. Primary and secondary prevention is key to reducing death and disability from VTE. How to make use of our current knowledge of inherited risk of VTE for primary and secondary disease prevention is not straightforward. This despite the fact that in the past two or three decades we have made major strides in enlarging our understanding of inherited VTE risk, and that new inherited risk factors continue to be identified.

For primary prevention of VTE genetic testing is not likely to play a role in the future. Genetic variations also determine recurrence risk, albeit that the effect sizes for individual genetic variations are invariably lower than those for first VTE events. Multilocus genetic risk scores improve risk classification, and it is now possible to stratify patients who have had a first venous thrombosis, into subgroups with a high and low risk of recurrence. Whether this approach can be used to tailor intensity and duration of treatment remains to be established.

Zusammenfassung

Venöse Thromboembolien (VTE) stellen weltweit eine gesundheitliche Belastung für Millionen Menschen dar. Die jährliche Inzidenz symptomatischer VTE, ein Sammelbegriff für tiefe Venenthrombosen, Lungenembolien oder beides, beträgt 2–3 je 1000 Einwohner. Die Ein-Jahres-Mortalität liegt bei 20% nach einer ersten VTE. Bei 15–25% der Überlebenden tritt innerhalb von drei Jahren nach dem ersten Ereignis eine VTE-Rezidivepisode auf. Primär- und Sekundärprophylaxe haben zentrale Bedeutung für die Reduktion der Mortalität und Behinderung durch VTE. Unser aktuelles Wissen zu angeborene VTE-Risiken kann nicht direkt für die Primärund Sekundärprophylaxe genutzt werden, obgleich wir diesen in den vergangenen zwei oder drei Jahrzehnten viel besser verstanden haben und ständig neue erbliche Risikofaktoren identifiziert werden. Für die VTE-Primärprophylaxe werden Gentests künftig vermutlich keine Rolle spielen. Genvariationen bestimmen das Rezidivrisiko, wenn auch die Effektgrößen bei individuellen Varianten grundsätzlich geringer sind als für erstmalige VTE-Ereignisse. Genetische Multilokus-Risiko-Scores verbessern die Klassifizierung und es ist möglich, Patienten nach der ersten Venenthrombose in Subgruppen mit hohem und niedrigem Rezidivrisiko zu stratifizieren. Ob dies dazu dienen kann, Intensität und Dauer der Behandlung zu individualisieren, ist noch zu klären.

Keywords

Venous thrombosis - thrombophilia - genetics - mutations

Schlüsselwörter

Venenthrombose - Thrombophilie - Genetik - Mutationen

• References

• 1 Lozano R, Naghavi M, Foreman K. et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010. Lancet 2012; 380: 2095-2128.
• 2 Raskob GE, Angchaisuksiri P, Blanco AN. et al. Thrombosis: a major contributor to the global disease burden. J Thromb Haemost 2014; 12: 1580-1590.
• 3 Reitsma PH, Versteeg HH, Middeldorp S. Mechanistic view of risk factors for venous thromboembolism. Arterioscler Thromb Vasc Biol 2012; 32: 563-568.
• 4 Debeij J, van Zaane B, Dekkers OM. et al. High levels of procoagulant factors mediate the association between free thyroxine and the risk of venous thrombosis. J Thromb Haemost 2014; 12: 839-846.
• 5 Stegeman BH, de Bastos M, Rosendaal FR. et al. Different combined oral contraceptives and the risk of venous thrombosis. BMJ. 2013 347. f5298.
• 6 Ay L, Kopp HP, Brix JM. et al. Thrombin generation in morbid obesity. J Thromb Haemost 2010; 08: 759-765.
• 7 Morelli VM, De Visser MC, Vos HL. et al. ABO blood group genotypes and the risk of venous thrombosis. J Thromb Haemost 2005; 03: 183-185.
• 8 Jick H, Slone D, Westerholm B. et al. Venous thromboembolic disease and ABO blood type. Lancet 1969; 01: 539-542.
• 9 Preston AE, Barr A. The plasma concentration of factor VIII in the normal population. Br J Haematol 1964; 10: 238-245.
• 10 Matsui T, Titani K, Mizuochi T. Structures of the asparagine-linked oligosaccharide chains of human von Willebrand factor. J Biol Chem 1992; 267: 8723-8731.
• 11 Egeberg O. Inherited antithrombin III deficiency causing thrombophilia. Thromb Diath Haemorrh 1965; 13: 516-530.
• 12 Griffin JH, Evatt B, Zimmerman TS. et al. Deficiency of protein C in congenital thrombotic disease. J Clin Invest 1981; 68: 1370-1373.
• 13 Comp PC, Nixon RR, Cooper MR. et al. Familial protein S deficiency is associated with recurrent thrombosis. J Clin Invest 1984; 74: 2082-2088.
• 14 Schwarz HP, Fischer M, Hopmeier P. Plasma protein S deficiency in familial thrombotic disease. Blood 1984; 64: 1297-1300.
• 15 De Visser MC, van Minkelen R, van Marion V. et al. Genome-wide linkage scan in affected sibling pairs identifies novel susceptibility region for venous thromboembolism. J Thromb Haemost 2013; 11: 1474-1484.
• 16 Middeldorp S. Is thrombophilia testing useful?. Hematology Am Soc Hematol Educ Program 2011; 150-155.
• 17 Pintao MC, Ribeiro DD, Bezemer ID. et al. Protein S levels and the risk of venous thrombosis. Blood 2013; 122: 3210-3219.
• 18 Vandenbroucke JP, Koster T, Briet E. et al. Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation. Lancet 1994; 344: 1453-1457.
• 19 Koeleman BP, Reitsma PH, Allaart CF. et al. Activated protein C resistance as an additional risk factor for thrombosis in protein C-deficient families. Blood 1994; 84: 1031-1035.
• 20 Koeleman BP, van Rumpt D, Hamulyak K. et al. Factor V Leiden: an additional risk factor for thrombosis in protein S deficient families?. Thromb Haemost 1995; 74: 580-583.
• 21 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.
• 22 Dahlbäck B, Carlsson M, Svensson PJ. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C. Proc Natl Acad Sci USA 1993; 90: 1004-1008.
• 23 Koster T, Rosendaal FR, De Ronde H. et al. Venous thrombosis due to poor anticoagulant response to activated protein C. Lancet 1993; 342: 1503-1506.
• 24 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.
• 25 Danckwardt S, Hartmann K, Gehring NH. et al. 3’ end processing of the prothrombin mRNA in thrombophilia. Acta Haematol 2006; 115: 192-197.
• 26 van Boven HH, Reitsma PH, Rosendaal FR. et al. Factor V Leiden in families with inherited antithrombin deficiency. Thromb Haemost 1996; 75: 417-421.
• 27 Uitte de Willige S, de Visser MC, Houwing-Duistermaat JJ. et al. Genetic variation in the fibrinogen gamma gene increases the risk for deep venous thrombosis by reducing plasma fibrinogen gamma’ levels. Blood 2005; 106: 4176-4183.
• 28 Zoller B, Li X, Sundquist J. et al. Age- and genderspecific familial risks for venous thromboembolism. Circulation 2011; 124: 1012-1020.
• 29 Tang W, Teichert M, Chasman DI. et al. A genomewide association study for venous thromboembolism. Genet Epidemiol 2013; 37: 512-521.
• 30 Bezemer ID, Bare LA, Doggen CJ. et al. Gene variants associated with deep vein thrombosis. JAMA 2008; 299: 1306-1314.
• 31 Tregouet DA, Heath S, Saut N. et al. Common susceptibility alleles are unlikely to contribute as strongly as the FV and ABO loci to VTE risk. Blood 2009; 113: 5298-5303.
• 32 Heit JA, Armasu SM, Asmann YW. et al. A genome-wide association study of venous thromboembolism identifies risk variants in chromosomes 1q24.2 and 9q. J Thromb Haemost 2012; 10: 1521-1531.
• 33 Dennis J, Johnson CY, Adediran AS. et al. The endothelial protein C receptor Ser219Gly variant and risk of common thrombotic disorders: a HuGE review and meta-analysis of evidence from observational studies. Blood 2012; 119: 2392-2400.
• 34 Meijers JC, Tekelenburg WL, Bouma BN. et al. High levels of coagulation factor XI as a risk factor for venous thrombosis. N Engl J Med 2000; 342: 696-701.
• 35 Franco RF, Reitsma PH. Genetic risk factors of venous thrombosis. Hum Genet 2001; 109: 369-384.
• 36 Morange PE, Bezemer I, Saut N. et al. A follow-up study of a genome-wide association scan identifies a susceptibility locus for venous thrombosis on chromosome 6p24.1. Am J Hum Genet 2010; 86: 592-595.
• 37 Baldwin Jr AS, LeClair KP, Singh H. et al. A large protein containing zinc finger domains binds to related sequence elements in the enhancers of the class I major histocompatibility complex and kappa immunoglobulin genes. Mol Cell Biol 1990; 10: 1406-1414.
• 38 Glynn RJ, Danielson E, Fonseca FA. et al. A randomized trial of rosuvastatin in the prevention of venous thromboembolism. N Engl J Med 2009; 360: 1851-1861.
• 39 Van der Velden PA, Krommenhoek-Van Es T, Allaart CF. et al. A frequent thrombomodulin amino acid dimorphism is not associated with thrombophilia. Thromb Haemost 1991; 65: 511-513.
• 40 Heit JA, Petterson TM, Owen WG. et al. Thrombomodulin gene polymorphisms or haplotypes as potential risk factors for venous thromboembolism. J Thromb Haemost 2005; 03: 710-717.
• 41 Navarro S, Medina P, Bonet E. 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.
• 42 Tang L, Wang HF, Lu X. et al. Common genetic risk factors for venous thrombosis in the Chinese population. Am J Hum Genet 2013; 92: 177-187.
• 43 Lotta LA, Tuana G, Yu J. 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.
• 44 de Haan HG, Bezemer ID, Doggen CJ. et al. Multiple SNP testing improves risk prediction of first venous thrombosis. Blood 2012; 120: 656-663.
• 45 Prandoni P, Noventa F, Ghirarduzzi A. et al. The risk of recurrent venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism. Haematologica 2007; 92: 199-205.
• 46 Van Hylckama Vlieg A, Flinterman LE, Bare LA. et al. Genetic variations associated with recurrent venous thrombosis. Circ Cardiovasc Genet. 2014 doi: 10.1161/CIRCGENETICS.114.000682.