Impact of thrombophilic gene mutations on thrombosis risk in patients with gastrointestinal carcinoma.
BACKGROUND
Patients with malignancies have an increased risk for thromboembolic events due to the release of tissue factor by the tumor, damage to the vessel wall, and immobilization. Moreover, tumors may improve their growth and metastatic spread by utilizing the coagulation system. To date, no information is available on the additional role of prothrombotic mutations in these patients.


METHODS
The prevalence of the factor V Leiden mutation (FVL) and the prothrombin G20210A mutation and of homozygosity for the methylenetetrahydrofolate reductase (MTHFR) C677T substitution has been analyzed in a cohort of 175 patients with gastrointestinal adenocarcinoma by the polymerase chain reaction-restriction fragment length polymorphism technique.


RESULTS
6.9% of the patients were heterozygous for FVL, 5.7% were heterozygous for the prothrombin mutation, and 9.7% were homozygous for the MTHFR C677T mutation was detected in 9.7% of patients. Compared with the normal population, we found an increased prevalence of the prothrombin G20210A substitution (5.7% vs. 0.8%, P = 0.028). Thromboses were absent in 147 patients (Group A), whereas 28 of the patients suffered from thromboses during the period following tumor diagnosis (Group B). In Group A, 6.8% of the patients and 21.4% of the patients in Group B had a thrombosis before the diagnosis of cancer (P = 0.025, odds ratio [OR] 3.7). Heterozygous FVL was present in 4.8% of the patients in Group A and in 17.9% of the patients in Group B (P = 0.026, OR 4.4). In patients with thromboses before the detection of the tumor, the risk was elevated 6.3-fold (25.0% vs 5.0%, P = 0.015). Heterozygosity for the prothrombin mutation and homozygosity for the MTHFR C677T substitution did not increase the incidence of thromboses.


CONCLUSIONS
We demonstrated a significant effect of FVL on thrombosis in patients with malignant disease. Most thromboses occurred during the first months after tumor diagnosis, implicating diagnostic and therapeutic procedures as important nongenetic risk factors for venous thromboembolism. Our data also indicate that the prothrombin G20210A mutation may be a possible cofactor in cancer pathogenesis.
Pihusch
Rudolf
R
Medizinische Klinik III-Grosshadern, Klinikum der Ludwig-Maximilians-Universität, München, Germany. Rudolf.Pihusch@med3.med.uni-muenchen.de
Danzl
Gudrun
G
Scholz
Michael
M
Harich
Detlev
D
Pihusch
Markus
M
Lohse
Peter
P
Hiller
Erhard
E
D000230:Adenocarcinoma / Q000150:complications* / Q000235:genetics / Q000401:mortality; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005165:Factor V / Q000235:genetics*; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000150:complications* / Q000235:genetics / Q000401:mortality; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D011516:Prothrombin / Q000235:genetics*; D012306:Risk; D013923:Thromboembolism / Q000209:etiology*
C095381:factor V Leiden; D005165:Factor V; D011516:Prothrombin