Advertisement

Molecular Medicine

, Volume 13, Issue 1–2, pp 112–120 | Cite as

Factor XIIIA-V34L and Factor XIIIB-H95R Gene Variants: Effects on Survival in Myocardial Infarction Patients

  • Donato Gemmati
  • Federica Federici
  • Gianluca Campo
  • Silvia Tognazzo
  • Maria L. Serino
  • Monica De Mattei
  • Marco Valgimigli
  • Patrizia Malagutti
  • Gabriele Guardigli
  • Paolo Ferraresi
  • Francesco Bernardi
  • Roberto Ferrari
  • Gian L. Scapoli
  • Linda Catozzi
Research Article

Abstract

It has been demonstrated recently that coagulation factor XIII (FXIII) plays an extraordinary role in myocardial healing after infarction, improving survival in a mouse model. Common FXIII gene variants (i.e. FXIIIA-V34L and FXIIIB-H95R) significantly influence the molecular activity. To evaluate whether there is a relationship between the two FXIII gene variants and survival in patients after myocardial infarction (MI), V34L and H95R were PCR-genotyped in a cohort of 560 MI cases and follow-up was monitored. Cases with ST-segment elevation MI (STEMI) were 416 (74.3%) and 374 of these were treated with primary percutaneous coronary intervention (PCI) (89.9%). The remaining 144 patients showed non-ST-segment elevation MI (NSTEMI) at enrollment. The combined endpoint was the occurrence of death, re-infarction, and heart failure. Kaplan-Meier analysis at one year yielded an overall rate for adverse events of 24.5% with a lower incidence in the L34-carriers (28.8% vs 17.1%; log-rank, P = 0.00025), similar to that of the 416 STEMI (23.8%) being (28.0% and 16.9%; VV34- and L34-carriers respectively; log-rank, P = 0.001). Primary PCI-group had a slight lower incidence (22.9%) of adverse events (26.8% and 17.1%; VV34- and L34-carriers respectively; log-rank, P= 0.009). During hospitalization, 506 patients received PCI (374 primary PCI and 132 elective PCI). Significance was conserved also in the overall PCI-group (28.6% and 17.8%; VV34- and L34-carriers respectively; log-rank, P = 0.001). Similar findings were observed at 30 days follow-up. Cases carrying both FXIII variants had improved survival rate (log-rank, P = 0.019). On the other hand, minor bleeding complications were found increased in L34-carriers (P = 0.0001) whereas major bleeding complications were not. Finally, more direct evidence on the role of FXIII molecule on survival might come from the fact that despite significant FXIII antigen reductions observed in cases after MI, regardless the FXIII genotype considered, L34-carriers kept almost normal FXIII activity (VV34- vs L34-carriers; P < 0.001). We conclude that FXIII L34-allele improves survival after MI in all the groups analyzed, possibly through its higher activity associated with assumable positive effects on myocardial healing and recovered functions. Genetically determined higher FXIII activity might influence post-MI outcome. This paves the way for using FXIII molecules to improve myocardial healing, recovery of functions, and survival after infarction.

Notes

Acknowledgments

This study was supported in part by the Italian MIUR funds and by a grant from Fondazione Cassa di Risparmio di Cento, Italy.

References

  1. 1.
    Nahrendorf M et al. (2006) Factor XIII deficiency causes cardiac rupture, impairs wound healing, and aggravates cardiac remodeling in mice with myocardial infarction. Circulation. 113:1196–202.CrossRefGoogle Scholar
  2. 2.
    Dardik R et al. (2006) Evaluation of the pro-angiogenic effect of factor XIII in heterotopic mouse heart allografts and FXIII-deficient mice. Thromb. Haemost. 95:546–50.CrossRefGoogle Scholar
  3. 3.
    Dardik R et al. (2003) Novel proangiogenic effect of factor XIII associated with suppression of thrombospondin 1 expression. Arterioscler. Thromb. Vasc. Biol. 23:1472–7.CrossRefGoogle Scholar
  4. 4.
    Dardik R, Loscalzo J, Inbal A. (2006) Factor XIII (FXIII) and angiogenesis. J. Thromb. Haemost. 1:19–25.CrossRefGoogle Scholar
  5. 5.
    Herouy Y, Hellstern MO, Vanscheidt W, Schopf E, Norgauer J. (2000) Factor XIII-mediated inhibition of fibrinolysis and venous leg ulcers. Lancet 355:1970–1.CrossRefGoogle Scholar
  6. 6.
    Brown LF et al. (1993) Fibroblast migration in fibrin gel matrices. Am. J. Pathol. 142:273–83.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Gemmati D et al. (2004) Factor XIII V34L polymorphism modulates the risk of chronic venous leg ulcer progression and extension. Wound Repair Regen. 12:512–7.CrossRefGoogle Scholar
  8. 8.
    Gemmati D et al. (2006) Influence of gene polymorphisms in ulcer healing process after superficial venous surgery. J. Vasc. Surg. 44:554–62.CrossRefGoogle Scholar
  9. 9.
    Keeley EC, Grines CL. (2004) Primary percutaneous coronary intervention for every patient with ST segment elevation myocardial infarction: what stands in the way? Ann. Intern. Med. 141:298–304.CrossRefGoogle Scholar
  10. 10.
    Radke PW, Kaiser A, Frost C, Sigwart U. (2003) Outcome after treatment of coronary in-stent restenosis; results from a systematic review using meta-analysis techniques. Eur. Heart J. 24:266–73.CrossRefGoogle Scholar
  11. 11.
    Stone GW et al. (1999) Clinical and angiographic follow-up after primary stenting in acute myocardial infarction: the Primary Angioplasty in Myocardial Infarction (PAMI) stent pilot trial. Circulation. 99:1548–54.CrossRefGoogle Scholar
  12. 12.
    Heggunje PS et al. (2004) Procedural success versus clinical risk status in determining discharge of patients after primary angioplasty for acute myocardial infarction. J. Am. Coll. Cardiol. 44:1400–7.CrossRefGoogle Scholar
  13. 13.
    Magid DJ et al. (2005) Relationship between time of day, day of week, timeliness of reperfusion, and in-hospital mortality for patients with acute ST-segment elevation myocardial infarction. JAMA. 294:803–12.CrossRefGoogle Scholar
  14. 14.
    Marcucci R et al. (2006) PAI-1 and homocysteine, but not lipoprotein (a) and thrombophilic polymorphisms, are independently associated with the occurrence of major adverse cardiac events after successful coronary stenting. Heart. 92:337–81.Google Scholar
  15. 15.
    Roldan V, Corral J, Marin F, Rivera J, Vicente V. (2002) Effect of factor XIII Val34Leu polymorphism on thrombolytic therapy in premature myocardial infarction. Thromb. Haemost. 88:354–5.CrossRefGoogle Scholar
  16. 16.
    Marin F et al. (2005) A pharmacogenetic effect of factor XIII valine 34 leucine polymorphism on fibrinolytic therapy for acute myocardial infarction. J. Am. Coll. Cardiol. 45:25–9.CrossRefGoogle Scholar
  17. 17.
    Ichinose A. (2001) Physiopathology and regulation of factor XIII. Thromb. Haemost. 86:57–65.CrossRefGoogle Scholar
  18. 18.
    Bereczky Z, Katona E, Muszbek L. (2003–2004) Fibrin stabilization (factor XIII), fibrin structure and thrombosis. Pathophysiol. Haemost. Thromb. 33:430–7.CrossRefGoogle Scholar
  19. 19.
    Fatah K et al. (1996) Proneness to formation of tight and rigid fibrin gel structures in men with myocardial infarction at a young age. Thromb. Haemost. 76:535–40.CrossRefGoogle Scholar
  20. 20.
    Kohler HP, Ariens RA, Whitaker P, Grant PJ. (1998) A common coding polymorphism in the FXIII A-subunit gene (FXIII Val34Leu) affects cross-linking activity. Thromb. Haemost. 80:704.CrossRefGoogle Scholar
  21. 21.
    Ariens RA et al. (2000) The factor XIII V34L polymorphism accelerates thrombin activation of factor XIII and affects cross-linked fibrin structure. Blood. 96:988–95.PubMedGoogle Scholar
  22. 22.
    Kohler HP et al. (1998) Association of a common polymorphism in the factor XIII gene with myocardial infarction. Thromb. Haemost. 79:8–13.CrossRefGoogle Scholar
  23. 23.
    Wartiovaara U et al. (1999) Association of FXIII Val34Leu with decreased risk of myocardial infarction in Finnish males. Atherosclerosis. 142:295–300.CrossRefGoogle Scholar
  24. 24.
    Gemmati D et al. (2001) A common mutation in the gene for coagulation factor XIII-A (Val34Leu): a risk factor for primary intracerebral hemorrhage is protective against atherothrombotic diseases. Am. J. Hematol. 67:183–8.CrossRefGoogle Scholar
  25. 25.
    Martini CH, Doggen CJ, Cavallini C, Rosendaal FR, Mannucci PM. (2005) No effect of polymorphisms in prothrombotic genes on the risk of myocardial infarction in young adults without cardiovascular risk factors. J. Thromb. Haemost. 3:177–9.CrossRefGoogle Scholar
  26. 26.
    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. 107:1117–22.CrossRefGoogle Scholar
  27. 27.
    Warner D, Mansfield MW, Grant PJ. (2001) Coagulation factor XIII and cardiovascular disease in UK Asian patients undergoing coronary angiography. Thromb. Haemost. 85:408–11.CrossRefGoogle Scholar
  28. 28.
    Komanasin N et al. (2005) Anovel polymorphism in the factor XIII B-subunit (His95Arg): relationship to subunit dissociation and venous thrombosis. J. Thromb. Haemost. 3:2487–96.CrossRefGoogle Scholar
  29. 29.
    Reiner AP et al. (2003) Genetic variants of coagulation factor XIII, postmenopausal estrogen therapy, and risk of nonfatal myocardial infarction. Blood. 102:25–30.CrossRefGoogle Scholar
  30. 30.
    Doggen CJ, Reiner AP, Vos HL, Rosendaal FR. (2003) Two factor XIII gene polymorphisms associated with a structural and functional defect and the risk of myocardial infarction in men. J. Thromb. Haemost. 1:2056–8.CrossRefGoogle Scholar
  31. 31.
    Anwar R et al. (1999) Genotype/phenotype correlations for coagulation factor XIII: specific normal polymorphisms are associated with high or low factor XIII specific activity. Blood. 93:897–905.PubMedGoogle Scholar
  32. 32.
    de Lange M et al. (2006) Joint linkage and association of six single-nucleotide polymorphisms in the factor XIII-A subunit gene, point to V34L as the main functional locus. Arterioscler. Thromb. Vasc. Biol. 26:1914–9.CrossRefGoogle Scholar
  33. 33.
    Kohler HP, Ariens RA, Whitaker P, Grant PJ. (1998) A common coding polymorphism in the FXIII A-subunit gene (FXIIIVal34Leu) affects cross-linking activity. Thromb. Haemost. 80:704.CrossRefGoogle Scholar
  34. 34.
    American College of Cardiology/American Heart Association Task Force on Practice Guidelines. (2006) (ACC/AHA/SCAI Writing Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention). Circulation. 113:156–75.CrossRefGoogle Scholar
  35. 35.
    Ballerini G, Gemmati D, Moratelli S, Morelli P, Serino ML. (1995) A photometric method for the dosage of factor XIII applied to the study of chronic hepatopathies. Thromb. Res. 78:451–6.CrossRefGoogle Scholar
  36. 36.
    Chew DP, Bhatt DL, Lincoff AM, Wolski K, Topol EJ. (2006) Clinical end point definitions following percutaneous coronary intervention and their relationship to late mortality: an assessment by attributable risk. Heart. 92:945–50.CrossRefGoogle Scholar
  37. 37.
    Alkjaersig N, Fletcher AP, Lewis M, Ittyerah R. (1977) Reduction of coagulation factor XIII concentration in patients with myocardial infarction, cerebral infarction, and other thromboembolic disorders. Thromb. Haemost. 38:863–73.CrossRefGoogle Scholar
  38. 38.
    Lim BC, Ariens RA, Carter AM, Weisel JW, Grant PJ. (2003) Genetic regulation of fibrin structure and function: complex gene-environment interactions may modulate vascular risk. Lancet. 361:1424–31.CrossRefGoogle Scholar
  39. 39.
    Trumbo TA, Maurer MC. (2000) Examining thrombin hydrolysis of the factor XIII activation peptide segment leads to a proposal for explaining the cardioprotective effects observed with the factor XIII V34L mutation. J. Biol. Chem. 275:20627–31.CrossRefGoogle Scholar
  40. 40.
    Maurer MC, Trumbo TA, Isetti G, Turner BT Jr. (2006) Probing interactions between the coagulants thrombin, Factor XIII, and fibrin(ogen). Arch. Biochem. Biophys. 445:36–45.CrossRefGoogle Scholar
  41. 41.
    Segev A et al. (2004) Thr325Ile polymorphism of the TAFI gene is related to TAFI antigen plasma levels and angiographic restenosis after percutaneous coronary interventions. Thromb. Res. 114:137–41.CrossRefGoogle Scholar
  42. 42.
    Botto N et al. (2004) C677T polymorphism of the methylenetetrahydrofolate reductase gene is a risk factor of adverse events after coronary revascularization. Int. J. Cardiol. 96:341–5.CrossRefGoogle Scholar
  43. 43.
    Toyofyuku M et al. (2002) Influence of angiotensinogen M253T gene polymorphism and an angiotensin converting enzyme inhibitor on restenosis after percutaneous coronary intervention. Atherosclerosis. 160:339–44.CrossRefGoogle Scholar
  44. 44.
    Ertl G, Frantz S. (2005) Healing after myocardial infarction. Cardiovasc. Res. 66:22–32.CrossRefGoogle Scholar
  45. 45.
    Inbal A et al. (2005) Impaired wound healing in factor XIII deficient mice. Thromb. Haemost. 94:432–7.PubMedGoogle Scholar
  46. 46.
    Zamboni P et al. (2004) Factor XIII contrasts the effects of metalloproteinases in human dermal fibroblast cultured cells. Vasc. Endovascular. Surg. 38:431–8.CrossRefGoogle Scholar
  47. 47.
    Tognazzo S et al. (2006) Prognostic role of factor XIII gene variants in chronic venous leg ulcer. J. Vasc. Surg. 44:815–9.CrossRefGoogle Scholar
  48. 48.
    Nahrendorf M, Weissleder R, Ertl G. (2006) Does FXIII deficiency impair wound healing after myocardial infarction? PLoS ONE 20;1:e48.CrossRefGoogle Scholar

Copyright information

© Feinstein Institute for Medical Research 2007

Authors and Affiliations

  • Donato Gemmati
    • 1
  • Federica Federici
    • 1
  • Gianluca Campo
    • 3
    • 4
  • Silvia Tognazzo
    • 1
  • Maria L. Serino
    • 1
  • Monica De Mattei
    • 1
  • Marco Valgimigli
    • 3
    • 4
  • Patrizia Malagutti
    • 3
    • 4
  • Gabriele Guardigli
    • 3
    • 4
  • Paolo Ferraresi
    • 2
  • Francesco Bernardi
    • 2
  • Roberto Ferrari
    • 3
    • 4
  • Gian L. Scapoli
    • 1
  • Linda Catozzi
    • 1
  1. 1.Center Study Haemostasis and Thrombosis, Department of Biomedical Sciences and Advanced TherapiesUniversity of FerraraFerraraItaly
  2. 2.Department of Biochemistry & Molecular BiologyUniversity of FerraraFerraraItaly
  3. 3.Chair of CardiologyUniversity of FerraraFerraraItaly
  4. 4.Cardiovascular Research CentreSalvatore Maugeri Foundation, IRCCS GussagoFerraraItaly

Personalised recommendations