Tissue Factor Expression As a Prognostic Marker in Patients with B-Cell Malignant Lymphoma

Background. Studies in tumor cell lines have shown an increased expression of TF. Expression of TF in adenocarcinoma of the pancreas is associated with tumor progression. It has been described that between 5% and 10% of patients with malignant lymphoma (ML) may develop VTD. The mechanisms of ML-associated thrombosis are unknown, however, expression of functional TF may increase as much as 75-fold in peripheral blood monocytes, particularly during relapse. As expected, thrombosis was found in patients with the highest TF levels. The role of TF in the biology of ML has not yet been determined. Considering indirect evidence, it seems that, besides its procoagulant effects, TF may have a role in tumor progression.

Objective. The purpose of the present study was to elucidate whether the interaction of tissue factor and TF/VIIa could induce relapsed in non Hodgkin Lymphoma patients.

Patients and Methods. We therefore performed a prospective study (cohort) to evaluate the risk of TF in non Hodgkin Lymphoma patients without a previous episode of venous thromboembolism. 59 patients 30 women and 29 men were enrolled in this study. The median age was 43.3 ± 14.5 (range 20 to 59). The TF and FT/VIIa activity was performed on fresh plasma (American Diagnostics, USA), and other tests (PC, PS, AT and activated protein C resistance) (STAGO, Asnieres, Francia).

Results.59 patients with B-cell ML, 30 women and 29 men with a mean age of 43.3 years (ranges 20 to 59). According to the Ann Arbor Staging system, 44% percent of patients (n=26) had a stage IV and only 14% at stage I. ML was mostly limited to lymph nodes (74%).

Results of hemostatic markers were between the normal ranges. However, concentrations of factors involved in the initiation phase of fluid phase of blood coagulation (TF, FT/VIIa complex, and FVII) had an abnormal distribution. None case with APCR was found.

Comparison between complete remission and relapsing patients. Thirty-one patients (52.5%) achieved complete remission at the end of follow-up and 28 (47.5%) relapsed. Mean follow up for patients with complete remission was 48 months vs. 18 months for relapsing patients (p <0.001). After comparing TF concentrations between the groups, relapsing patients had higher levels of TF (p=0.005). TF/FVIIa complex levels were also significantly higher in patients with relapsing disease (p=0.019). As expected LDH levels were significantly lower in patients with complete remission (p=0.0001).

TF levels and response to treatment. Twenty-nine patients had normal TF levels. Relapses were more frequently found in patients with elevated TF concentrations (n=19) as compared with patients with normal TF levels (n=9) (p=0.013). Elevated TF/FVIIa complexes levels were also more frequently seen among patients with relapsing ML (n=32) as compared with patients with complete remission (n=27) (p=0.046).As expected, other factors associated with a poor prognosis were DHL levels (p=0.001) and IPI (p=0.001).

Discussion. TF and TF/FVIIIa concentrations were significantly different in patients who achieved complete remission as compared with those with relapse after treatment. As expected for the staging of patients included LDH serum levels as well as IPI score were also significantly different between these two groups of patients. Moreover, estimation of the relative risks associated with relapsing disease showed that also these four variables were associated with relapsing disease. However, linear regression analysis showed that TF, LDH, and IPI but not TF/FVIIa complexes remained as a risk factor for relapse in patients with ML. To our knowledge, we have demonstrated for the first time that high TF concentration is a prognosis factor for relapse in patients with B-cell ML.

Our results seem consistent with previous reports regarding an association between the increased TF expression and advanced staging of the malignant disease. It has been demonstrated the presence of high plasma levels of TF and FVIII in patients with solid tumors suggesting that it may be an important mechanism to activate blood coagulation system in cancer patients. Tumor cells may also induce TF expression on the cell surface of peripheral blood monocytes and macrophages.