Tissue Factor-Related Biomarkers and Prediction of Cancer-Associated VTE: Correlative Analyses of the Phacs Trial

Background: Cancer patients at high or low risk for venous thromboembolism (VTE) can be predicted by a validated score (Khorana et al, Blood 2008) but the mechanisms underlying this association are not fully understood. We evaluated the association of VTE-related biomarkers with clinical outcomes in patients enrolled in a randomized trial of outpatient prophylaxis in high-risk patients and a control population of low-risk patients.

Methods: Cancer patients with risk score ≥3 starting systemic therapy were randomized to dalteparin or observation for 12 weeks; a low-risk group of controls (score=0) was concurrently enrolled. Analyses for tissue factor (TF) using microparticle procoagulant activity, TF pathway inhibitor (TFPI) using ELISA, D-dimer and factor VIIA were conducted on specimens obtained at enrollment and 4-weekly on study as well as at enrollment in control patients.

Results: The study populations comprised 89 randomized high-risk patients and 101 low-risk patients. TF MP-PCA levels were more likely to be detectable in high-risk patients (51.7% vs 32.7% of low-risk patients, p=0.01) and levels were elevated at time of enrollment in high-risk compared to low-risk patients (mean 0.67 vs 0.19 pg/mL in low-risk, p=0.002; median 0.03 vs 0 pg/mL, p=0.001). TF levels were particularly high in the subgroup of high-risk patients with pancreatic cancer (N=38, 57.9% detectable, mean 0.87 pg/mL, median 0.13 pg/mL). D-dimer levels were also significantly elevated in high-risk patients (median 1.23 vs 0.92 mg/mL, p=0.006). Levels of F1.2 and FVIIa were not significantly different between the high- and low-risk groups. Patients randomized to dalteparin had a significant decline in median D-dimer levels (median 1.22 mg/mL for timepoint 1 versus 0.7 mg/mL for timepoint 4, p =0.018) whereas there was no significant change over time for patients randomized to observation (median 1.30 vs 1.33 mg/mL, p=0.43). F1.2 levels also declined over time for patients randomized to dalteparin (median 77.17 to 32.37, p=0.01) but not for patients randomized to observation (median 59.06 to 61.63, p=0.99). In multivariate time-dependent Cox analysis in high-risk patients, VTE was associated with both doubling of TF (HR 1.42 95% CI 1.17-1.84, p=0.0003) and doubling of TFPI (HR 3.21, 95% CI 1.14-9.50, p=0.02).

Conclusions: Cancer patients at high-risk for VTE are more likely to have increased TF levels at baseline; increased levels of both TF and TFPI were associated with future VTE. Further investigations into the role of TF and TFPI in cancer-associated thrombosis and their roles as predictive biomarkers are warranted.