Skip to main content
SpringerLink
Log in

Factor XIII Val34Leu polymorphism and recurrent myocardial infarction in patients with coronary artery disease

  • Published:
Journal of Thrombosis and Thrombolysis Aims and scope Submit manuscript

Abstract

Factor XIII (FXIII) is necessary for cross linking of fibrin strands and generation of stable fibrin clot. FXIII Val34Leu is a common genetic single nucleotide polymorphism that has been associated with accelerated fibrin stabilization and reduced rate of fibrinolysis. The contribution of Val34Leu to long term risk of recurrent myocardial infarction (MI) in patients with coronary stenting has not been conclusively established. The objective of the study was to examine the effects of Val34Leu on fibrin generation, platelet aggregation, and long term clinical outcomes in patients with coronary artery disease treated with dual antiplatelet therapy. Patients with angiographically documented coronary artery disease who were treated with aspirin and clopidogrel were enrolled (n = 211). Light transmittance aggregometry and plasma fibrin clot formation using thrombelastography (TEG) were determined. Genotyping of Val34Leu was performed using Taqman assay. Clinical events during follow up were recorded. Homozygous carriers of 34Leu variant had significantly shorter fibrin clot formation time as compared to wild type individuals (TEG K: 1.27 ± 0.3 vs. 1.68 ± 1.1 min, p = 0.011). The Val34Leu variant was associated with gene dose dependent increased risk of MI (log rank, p = 0.002) or occurrence of composite of MI and CV death (log rank, p = 0.005) with highest event rates observed in homozygous carriers of 34Leu. In summary, FXIII Val34Leu polymorphism was associated with increased rate of fibrin stabilization in homozygous carriers of the variant and may increase risk of recurrent MI and death in patients with angiographically established coronary artery disease treated with dual antiplatelet therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Holmes DR Jr, Kereiakes DJ, Garg S, Serruys PW, Dehmer GJ, Ellis SG, Williams DO, Kimura T, Moliterno DJ (2010) Stent thrombosis. J Am Coll Cardiol 56:1357–1365

    Article  PubMed  Google Scholar 

  2. Gurbel PA, Bliden KP, Guyer K, Cho PW, Zaman KA, Kreutz RP, Bassi AK, Tantry US (2005) Platelet reactivity in patients and recurrent events post-stenting: results of the prepare post-stenting study. J Am Coll Cardiol 46:1820–1826

    Article  CAS  PubMed  Google Scholar 

  3. Price MJ, Berger PB, Teirstein PS, Tanguay JF, Angiolillo DJ, Spriggs D, Puri S, Robbins M, Garratt KN, Bertrand OF, Stillabower ME, Aragon JR, Kandzari DE, Stinis CT, Lee MS, Manoukian SV, Cannon CP, Schork NJ, Topol EJ, GRAVITAS Investigators (2011) Standard- vs. high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. JAMA 305:1097–1105

    Article  CAS  PubMed  Google Scholar 

  4. Jneid H, Anderson JL, Wright RS, Adams CD, Bridges CR, Casey DE Jr, Ettinger SM, Fesmire FM, Ganiats TG, Lincoff AM, Peterson ED, Philippides GJ, Theroux P, Wenger NK, Zidar JP, Anderson JL (2012) 2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/Non-ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 26:875–910

    Google Scholar 

  5. Libby P, Ridker PM, Hansson GK (2009) Inflammation in atherosclerosis: from pathophysiology to practice. J Am Coll Cardiol 54:2129–2138

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Emerging Risk Factors Collaboration, Kaptoge S, Di Angelantonio E, Lowe G, Pepys MB, Thompson SG, Collins R, Danesh J (2010) C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet 375:132–140

    Article  PubMed  Google Scholar 

  7. Park DW, Yun SC, Lee JY, Kim WJ, Kang SJ, Lee SW, Kim YH, Lee CW, Kim JJ, Park SW, Park SJ (2009) C-reactive protein and the risk of stent thrombosis and cardiovascular events after drug-eluting stent implantation. Circulation 120:1987–1995

    Article  CAS  PubMed  Google Scholar 

  8. Tantry US, Bliden KP, Suarez TA, Kreutz RP, Dichiara J, Gurbel PA (2010) Hypercoagulability, platelet function, inflammation and coronary artery disease acuity: results of the thrombotic risk progression (TRIP) study. Platelets 21:360–367

    Article  CAS  PubMed  Google Scholar 

  9. Gurbel PA, Bliden KP, Kreutz RP, Dichiara J, Antonino MJ, Tantry US (2009) The link between heightened thrombogenicity and inflammation: pre-procedure characterization of the patient at high risk for recurrent events after stenting. Platelets 20:97–104

    Article  CAS  PubMed  Google Scholar 

  10. Kreutz RP, Owens J, Breall JA, Lu D, von der Lohe E, Bolad I, Sinha A, Flockhart DA (2013) C-reactive protein and fibrin clot strength measured by thrombelastography after coronary stenting. Blood Coagul Fibrinol 24:321–326

    Article  CAS  Google Scholar 

  11. Deloukas P, Kanoni S, Willenborg C et al (2012) Large-scale association analysis identifies new risk loci for coronary artery disease. Nat Genet 45:25–33

    Article  PubMed  Google Scholar 

  12. Bagoly Z, Koncz Z, Hársfalvi J, Muszbek L (2012) Factor XIII, clot structure, thrombosis. Thromb Res 129:382–387

    Article  CAS  PubMed  Google Scholar 

  13. Schroeder V, Chatterjee T, Kohler HP (2001) Influence of blood coagulation factor XIII and FXIII Val34Leu on plasma clot formation measured by thrombelastography. Thromb Res 104:467–474

    Article  CAS  PubMed  Google Scholar 

  14. Silvain J, Pena A, Vignalou JB, Hulot JS, Galier S, Cayla G, Bellemain-Appaix A, Barthélémy O, Beygui F, Bal-dit-Sollier C, Drouet L, Weisel JW, Montalescot G, Collet JP (2011) FXIII-A Leu34 genetic variant in premature coronary artery disease: a genotype–phenotype case control study. Thromb Haemost 106:511–520

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Ariëns RA, Philippou H, Nagaswami C, Weisel JW, Lane DA, Grant PJ (2000) The factor XIII V34L polymorphism accelerates thrombin activation of factor XIII and affects cross-linked fibrin structure. Blood 96:988–995

    PubMed  Google Scholar 

  16. Magwenzi SG, Ajjan RA, Standeven KF, Parapia LA, Naseem KM (2011) Factor XIII supports platelet activation and enhances thrombus formation by matrix proteins under flow conditions. J Thromb Haemost 9:820–833

    Article  CAS  PubMed  Google Scholar 

  17. Kreutz RP, Tantry US, Bliden KP, Gurbel PA (2007) Inflammatory changes during the ‘common cold’ are associated with platelet activation and increased reactivity of platelets to agonists. Blood Coagul Fibrinol 18:713–718

    Article  CAS  Google Scholar 

  18. Thygesen K, Alpert JS, White HD (2007) Joint ESC, ACCF, AHA, WHF Task Force for the redefinition of myocardial infarction, universal definition of myocardial infarction. Circulation 116:2634–2653

    Article  PubMed  Google Scholar 

  19. Rao SV, O’Grady K, Pieper KS, Granger CB, Newby LK, Mahaffey KW, Moliterno DJ, Lincoff AM, Armstrong PW, Van de Werf F, Califf RM, Harrington RA (2006) A comparison of the clinical impact of bleeding measured by two different classifications among patients with acute coronary syndromes. J Am Coll Cardiol 47:809–816

    Article  PubMed  Google Scholar 

  20. Aleksic N, Ahn C, Wang YW, Juneja H, Folsom AR, Boerwinkle E, Wu KK (2002) Factor XIIIA Val34Leu polymorphism does not predict risk of coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) Study. Arterioscler Thromb Vasc Biol 22:348–352

    Article  CAS  PubMed  Google Scholar 

  21. Atherosclerosis, Thrombosis, and Vascular Biology Italian Study Group (2003) No evidence of association between prothrombotic gene polymorphisms and the development of acute myocardial infarction at a young age. Circulation 107:1117–1122

    Article  Google Scholar 

  22. Bereczky Z, Balogh E, Katona E, Pocsai Z, Czuriga I, Széles G, Kárpáti L, Adány R, Edes I, Muszbek L (2007) Modulation of the risk of coronary sclerosis/myocardial infarction by the interaction between factor XIII subunit A Val34Leu polymorphism and fibrinogen concentration in the high risk Hungarian population. Thromb Res 120:567–573

    Article  CAS  PubMed  Google Scholar 

  23. Vokó Z, Bereczky Z, Katona E, Adány R, Muszbek L (2007) Factor XIII Val34Leu variant protects against coronary artery disease: a meta-analysis. Thromb Haemost 97:458–463

    PubMed  Google Scholar 

  24. Smith NL, Bis JC, Biagiotti S, Rice K, Lumley T, Kooperberg C, Wiggins KL, Heckbert SR, Psaty BM (2008) Variation in 24 hemostatic genes and associations with non-fatal myocardial infarction and ischemic stroke. J Thromb Haemost 6:45–53

    CAS  PubMed  Google Scholar 

  25. Marín F, González-Conejero R, Lee KW, Corral J, Roldán V, López F, Sogorb F, Caturla J, Lip GY, Vicente V (2005) A pharmacogenetic effect of factor XIII valine 34 leucine polymorphism on fibrinolytic therapy for acute myocardial infarction. J Am Coll Cardiol 45:25–29

    Article  PubMed  Google Scholar 

  26. Hernández-Romero D, Marín F, Lee KW, Roldán V, Caturla J, Corral J, Valdés M, Lip GY, Vicente V, González-Conejero R (2010) Synergism between factor XII-4C>T and factor XIII Val34Leu polymorphisms in fibrinolytic therapy in acute myocardial infarction. Thromb Haemost 104:650–652

    Article  PubMed  Google Scholar 

  27. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK (2001) Clopidogrel in unstable angina to prevent recurrent events trial investigators, effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 345:494–502

    Article  CAS  PubMed  Google Scholar 

  28. Iakovou I, Schmidt T, Bonizzoni E, Ge L, Sangiorgi GM, Stankovic G, Airoldi F, Chieffo A, Montorfano M, Carlino M, Michev I, Corvaja N, Briguori C, Gerckens U, Grube E, Colombo A (2005) Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA 293:2126

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported in part, by the Indiana Clinical and Translational Sciences Institute funded, in part by Grant Number (RR025761) from the National Institutes of Health, National Center for Research Resources, Clinical and Translational Sciences Award, as well as the Indiana University Health Values Grant, the Indiana University Health—Indiana University School of Medicine Strategic Research Initiative, and internal funding from the Department of Medicine, Indiana University School of Medicine, Indianapolis.

Disclosure

YJ is currently an employee of Eli & Lilly, Co. The other authors have no conflicts of interest to declare.

Author information

Authors and Affiliations

  1. Krannert Institute of Cardiology, Indiana University School of Medicine, 1800 N. Capitol Ave, ME-400, Indianapolis, IN, 46202, USA

    Rolf P. Kreutz, Abbas Bitar, Jeffrey A. Breall, Elisabeth von der Lohe, Anjan Sinha & Matteo Vatta

  2. Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, IN, USA

    Rolf P. Kreutz, Janelle Owens, Zeruesenay Desta, Perry Nystrom, Yan Jin & David A. Flockhart

  3. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA

    Matteo Vatta

Authors
  1. Rolf P. Kreutz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Abbas Bitar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Janelle Owens
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zeruesenay Desta
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jeffrey A. Breall
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Elisabeth von der Lohe
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Anjan Sinha
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Matteo Vatta
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Perry Nystrom
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yan Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. David A. Flockhart
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rolf P. Kreutz.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 633 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kreutz, R.P., Bitar, A., Owens, J. et al. Factor XIII Val34Leu polymorphism and recurrent myocardial infarction in patients with coronary artery disease. J Thromb Thrombolysis 38, 380–387 (2014). https://doi.org/10.1007/s11239-014-1059-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11239-014-1059-4

Keywords

Search

Navigation