Download PDF
Thromb Haemost 2011; 106(05): 908-913
DOI: 10.1160/TH11-04-0278
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

The role of fibrinogen plasma levels, the –455G>A fibrinogen and the factor XIII A subunit (FXIII-A) Val34Leu polymorphism in cancer-associated venous thrombosis

Vera Tiedje
1   Clinical Division of Haematology and Haemostaseology, Department of Medicine I, Medical University of Vienna, Austria
,
Daniela Dunkler
2   Center for Medical Statistics, Informatics and Intelligent Systems, Section for Clinical Biometrics, Medical University of Vienna, Austria
,
Cihan Ay
1   Clinical Division of Haematology and Haemostaseology, Department of Medicine I, Medical University of Vienna, Austria
,
Birgit Horvath
3   Department of Laboratory Medicine, Medical University of Vienna, Austria
,
Peter Quehenberger
3   Department of Laboratory Medicine, Medical University of Vienna, Austria
,
Magdalena Pabinger
1   Clinical Division of Haematology and Haemostaseology, Department of Medicine I, Medical University of Vienna, Austria
,
Christoph Zielinski
4   Clinical Division of Oncology, Department of Medicine I, Medical University of Vienna, Austria
,
Ingrid Pabinger
1   Clinical Division of Haematology and Haemostaseology, Department of Medicine I, Medical University of Vienna, Austria
,
Christine Mannhalter
3   Department of Laboratory Medicine, Medical University of Vienna, Austria
› Author Affiliations Financial support: This study was supported by a grant from the Jubiläumsfonds of the Austrian National Bank (project number 10935 and 12739) and by an unrestricted grant from Pfizer Austria.
Further Information

Publication History

Received: 28 April 2011

Accepted after minor revision: 22 July 2011

Publication Date:
23 November 2017 (online)

  PDF Download  Permissions and Reprints

Summary

Venous thromboembolism (VTE) is a life-threatening complication in cancer patients. Identification of risk factors has been in focus in the past years. Functional single nucleotide polymorphisms (SNP) of coagulation factors known to influence the concentration or function may be considered to influence the risk of VTE in cancer patients. We evaluated the influence of fibrinogen plasma levels, the –455G>A SNP in the fibrinogen beta gene and the Val34Leu (163G>T) SNP in the factor XIII A-subunit (FXIII-A) gene on the risk of VTE. In 1,079 tumour patients recruited for the prospective Vienna Cancer and Thrombosis Study (CATS) fibrinogen levels were determined by the Clauss method. The FXIII-A Val34Leu and the fibrinogen –455G>A SNPs were tested by allele-specific PCR. The median follow-up time was 604 days, 83 thrombotic events occurred. The median fibrinogen level was 381 mg/dl (25th-75th percentile: 312 to 467). In a multivariable Cox model adjusted to chemotherapy, surgery, radiotherapy, age and sex, neither the fibrinogen concentration (hazard ratio [HR] =1.05, confidence interval [CI] 0.839–1.310 p=0.68), nor the –455G>A SNP (HR=0.77, 95%CI 0.491–1.197; p=0.24), nor the Val34Leu SNP (HR=0.99, 95%CI 0.646–1.542 p=0.99) were associated with occurrence of VTE. The fibrinogen concentration was not significantly different among the fibrinogen –455G or A genotype carriers (p = 0.33). Disseminated intravascular coagulation was observed in only five patients, none of these developed VTE. In conclusion, fibrinogen plasma levels, the fibrinogen –455G>A and the FXIII-A Val34Leu polymorphisms were not associated with VTE in our study.

Keywords

Venous thromboembolism - cancer - fibrinogen - factor XIII-A Val34Leu SNP - fibrinogen –455G>A SNP
 

  • References

  • 1 Paneesha S, McManus A, Arya R. et al. Frequency, demographics and risk (according to tumour type or site) of cancer-associated thrombosis among patients seen at outpatient DVT clinics. Thromb Haemost 2010; 103: 338-343.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 2 Sood SL. Cancer-associated thrombosis. Curr Opin Hematol 2009; 16: 378-385.
    CrossrefPubMedGoogle Scholar
  • 3 Ay C, Vormittag R, Dunkler D. et al. D-dimer and prothrombin fragment 1 + 2 predict venous thromboembolism in patients with cancer: results from the Vienna Cancer and Thrombosis Study. J Clin Oncol 2009; 27: 4124-4129.
    CrossrefPubMedGoogle Scholar
  • 4 Ay C, Dunkler D, Marosi C. et al. Prediction of venous thromboembolism in cancer patients. Blood 2010; 116: 5377-5382.
    CrossrefPubMedGoogle Scholar
  • 5 Falanga A. Thrombophilia in cancer. Semin Thromb Hemost 2005; 31: 104-110.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 Palumbo JS, Talmage KE, Massari JV. et al. Platelets and fibrin(ogen) increase metastatic potential by impeding natural killer cell-mediated elimination of tumor cells. Blood 2005; 105: 178-185.
    CrossrefPubMedGoogle Scholar
  • 7 Salazar-Sanchez L, Leon MP, Cartin M. et al. The FXIIIVal34Leu, common and risk factors of venous thrombosis in early middle-age Costa Rican patients. Cell Biochem Funct 2007; 25: 739-745.
    CrossrefPubMedGoogle Scholar
  • 8 Flinterman LE, van Hylckama Vlieg A, Rosendaal FR. et al. Venous thrombosis of the upper extremity: effect of blood group and coagulation factor levels on risk. Br J Haematol 2010; 149: 118-123.
    CrossrefPubMedGoogle Scholar
  • 9 van Hylckama Vlieg A, Rosendaal FR. High levels of fibrinogen are associated with the risk of deep venous thrombosis mainly in the elderly. J Thromb Haemost 2003; 1: 2677-2678.
    CrossrefPubMedGoogle Scholar
  • 10 Leander K, Wiman B, Hallqvist J. et al. The G-455A polymorphism of the fibrinogen Bbeta-gene relates to plasma fibrinogen in male cases, but does not interact with environmental factors in causing myocardial infarction in either men or women. J Intern Med 2002; 252: 332-341.
    CrossrefPubMedGoogle Scholar
  • 11 Shojaie M, Pourahmad M, Eshraghian A. et al. Fibrinogen as a risk factor for premature myocardial infarction in Iranian patients: a case control study. Vasc Health Risk Manag 2009; 5: 673-676.
    PubMedGoogle Scholar
  • 12 Sun A, Ma H, Xu D. et al. Association between -455G/A and fibrinogen in a Chinese population. Acta Cardiol 2009; 64: 357-361.
    CrossrefPubMedGoogle Scholar
  • 13 Sturgeon JD, Folsom AR, Longstreth Jr. WT. et al. Hemostatic and inflammatory risk factors for intracerebral hemorrhage in a pooled cohort. Stroke 2008; 39: 2268-2273.
    CrossrefPubMedGoogle Scholar
  • 14 Jood K, Danielson J, Ladenvall C. et al. Fibrinogen gene variation and ischemic stroke. J Thromb Haemost 2008; 6: 897-904.
    CrossrefPubMedGoogle Scholar
  • 15 Beg M, Nizami A, Singhal KC. et al. Role of serum fibrinogen in patients of ischemic cerebrovascular disease. Nepal Med Coll J 2007; 9: 88-92.
    PubMedGoogle Scholar
  • 16 Sallah S, Wan JY, Nguyen NP. et al. Disseminated intravascular coagulation in solid tumors: clinical and pathologic study. Thromb Haemost 2001; 86: 828-833.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 17 Mosesson MW. Fibrinogen and fibrin structure and functions. J Thromb Haemost 2005; 3: 1894-1904.
    CrossrefPubMedGoogle Scholar
  • 18 Mosesson MW, Siebenlist KR, Meh DA. The structure and biological features of fibrinogen and fibrin. Ann NY Acad Sci 2001; 936: 11-30.
    PubMedGoogle Scholar
  • 19 Litvinov RI, Gorkun OV, Galanakis DK. et al. Polymerization of fibrin: Direct observation and quantification of individual B:b knob-hole interactions. Blood 2007; 109: 130-138.
    CrossrefPubMedGoogle Scholar
  • 20 Kant JA, Fornace Jr. AJ, Saxe D. et al. Evolution and organization of the fibrinogen locus on chromosome 4: gene duplication accompanied by transposition and inversion. Proc Natl Acad Sci USA 1985; 82: 2344-2348.
    CrossrefPubMedGoogle Scholar
  • 21 van't Hooft FM, von Bahr SJ, Silveira A. et al. Two common, functional polymorphisms in the promoter region of the beta-fibrinogen gene contribute to regulation of plasma fibrinogen concentration. Arterioscler Thromb Vasc Biol 1999; 19: 3063-3070.
    CrossrefPubMedGoogle Scholar
  • 22 Siegerink B, Rosendaal FR, Algra A. Genetic variation in fibrinogen; its relationship to fibrinogen levels and the risk of myocardial infarction and ischemic stroke. J Thromb Haemost 2009; 7: 385-390.
    CrossrefPubMedGoogle Scholar
  • 23 Pongracz E, Andrikovics H, Csornai M. et al. Contribution of the -455G/A polymorphism at beta-fibrinogen gene and of the Leiden mutation to hemorheological parameters in ischemic stroke patients. Clin Hemorheol Microcirc 2006; 35: 75-82.
    PubMedGoogle Scholar
  • 24 Folsom AR, Aleksic N, Ahn C. et al. Beta-fibrinogen gene -455G/A polymorphism and coronary heart disease incidence: the Atherosclerosis Risk in Communities (ARIC) Study. Ann Epidemiol 2001; 11: 166-170.
    CrossrefPubMedGoogle Scholar
  • 25 Renner W, Cichocki L, Forjanics A. et al. G-455A polymorphism of the fibrinogen beta gene and deep vein thrombosis. Eur J Clin Invest 2002; 32: 755-758.
    CrossrefPubMedGoogle Scholar
  • 26 Chen X, Xu M, Jin L. et al. Association of beta-fibrinogen gene -148C/T and -455G/A polymorphisms and coronary artery disease in Chinese population: a meta analysis. Sci China C Life Sci 2008; 51: 814-820.
    CrossrefPubMedGoogle Scholar
  • 27 Harrington DJ, Malefora A, Schmeleva V. et al. Genetic variations observed in arterial and venous thromboembolism--relevance for therapy, risk prevention and prognosis. Clin Chem Lab Med 2003; 41: 496-500.
    PubMedGoogle Scholar
  • 28 Siebenlist KR, Meh DA, Mosesson MW. Protransglutaminase (factor XIII) mediated crosslinking of fibrinogen and fibrin. Thromb Haemost 2001; 86: 1221-1228.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 29 Komaromi I, Bagoly Z, Muszbek L. Factor XIII: novel structural and functional aspects. J Thromb Haemost 2011; 9: 9-20.
    CrossrefPubMedGoogle Scholar
  • 30 Palumbo JS, Barney KA, Blevins EA. et al. Factor XIII transglutaminase supports hematogenous tumor cell metastasis through a mechanism dependent on natural killer cell function. J Thromb Haemost 2008; 6: 812-819.
    CrossrefPubMedGoogle Scholar
  • 31 Muszbek L, Bagoly Z, Bereczky Z. et al. The involvement of blood coagulation factor XIII in fibrinolysis and thrombosis. Cardiovasc Hematol Agents Med Chem 2008; 6: 190-205.
    CrossrefPubMedGoogle Scholar
  • 32 Ichinose A, Davie EW. Primary structure of human coagulation factor XIII. Adv Exp Med Biol 1988; 231: 15-27.
    PubMedGoogle Scholar
  • 33 Catto AJ, Kohler HP, Coore J. et al. Association of a common polymorphism in the factor XIII gene with venous thrombosis. Blood 1999; 93: 906-908.
    PubMedGoogle Scholar
  • 34 Gohil R, Peck G, Sharma P. The genetics of venous thromboembolism. A meta-analysis involving approximately 120,000 cases and 180,000 controls. Thromb Haemost 2009; 102: 360-370.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 35 Wells PS, Anderson JL, Scarvelis DK. et al. Factor XIII Val34Leu variant is protective against venous thromboembolism: a HuGE review and meta-analysis. Am J Epidemiol 2006; 164: 101-109.
    CrossrefPubMedGoogle Scholar
  • 36 Bereczky Z, Muszbek L. Factor XIII and venous thromboembolism. Semin Thromb Hemost 2011; 37: 305-314.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 37 Ay C, Simanek R, Vormittag R. et al. High plasma levels of soluble P-selectin are predictive of venous thromboembolism in cancer patients: results from the Vienna Cancer and Thrombosis Study (CATS). Blood 2008; 112: 2703-2708.
    CrossrefPubMedGoogle Scholar
  • 38 Holzer G, Grasse AV, Zehetmayer S. et al. Vitamin K epoxide reductase (VKORC1) gene mutations in osteoporosis: A pilot study. Transl Res 2010; 156: 37-44.
    CrossrefPubMedGoogle Scholar
  • 39 Schemper M, Smith TL. A note on quantifying follow-up in studies of failure time. Control Clin Trials 1996; 17: 343-346.
    CrossrefPubMedGoogle Scholar
  • 40 Danesh J, Lewington S, Thompson SG. et al. Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: an individual participant meta-analysis. J Am Med Assoc 2005; 294: 1799-1809.
    PubMedGoogle Scholar
  • 41 Koster T, Rosendaal FR, Reitsma PH. 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.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 42 Tsai AW, Cushman M, Rosamond WD. et al. Coagulation factors, inflammation markers, and venous thromboembolism: the longitudinal investigation of thromboembolism etiology (LITE). Am J Med 2002; 113: 636-642.
    CrossrefPubMedGoogle Scholar
  • 43 Kanz R, Vukovich T, Vormittag R. et al. Thrombosis risk and survival in cancer patients with elevated C-reactive protein. J Thromb Haemost 2011; 9: 57-63.
    CrossrefPubMedGoogle Scholar
  • 44 Vormittag R, Simanek R, Ay C. et al. High factor VIII levels independently predict venous thromboembolism in cancer patients: the cancer and thrombosis study. Arterioscler Thromb Vasc Biol 2009; 29: 2176-2181.
    CrossrefPubMedGoogle Scholar
  • 45 de Maat MP. Effects of diet, drugs, and genes on plasma fibrinogen levels. Ann NY Acad Sci 2001; 936: 509-521.
    PubMedGoogle Scholar
  • 46 Lim BC, Ariens RA, Carter AM. et al. Genetic regulation of fibrin structure and function: complex gene-environment interactions may modulate vascular risk. Lancet 2003; 361: 1424-1431.
    CrossrefPubMedGoogle Scholar
  • 47 Bereczky Z, Balogh E, Katona E. et al. 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 2007; 120: 567-573.
    CrossrefPubMedGoogle Scholar
  • 48 Ramacciotti E, Wolosker N, Puech-Leao P. et al. Prevalence of factor V Leiden, FII G20210A, FXIII Val34Leu and MTHFR C677T polymorphisms in cancer patients with and without venous thrombosis. Thromb Res 2003; 109: 171-174.
    CrossrefPubMedGoogle Scholar