Tissue Factor Pathway Inhibitor is associated with risk of venous thromboembolism and all-cause mortality in patients with cancer

Introduction Venous thromboembolism (VTE) is a common complication in patients with cancer. Several biomarkers have been found to predict risk of VTE in patients with cancer. However, the role of natural inhibitors of haemostasis in cancer-associated VTE is less studied. Tissue factor pathway inhibitor (TFPI) is a natural anticoagulant that inhibits complexes of tissue factor and factor VIIa via its K1 domain and factor Xa via its K2 domain. Conflicting results about its association with VTE risk were reported in the general population, and it has been discussed whether TFPI may act as a surrogate marker for circulating TF levels. In comparison to the non-cancer population, higher TFPI levels were reported in patients with cancer. We aimed to investigate TFPI levels in patients with cancer and explore their association with risk of VTE and all-cause mortality.

Method Total TFPI antigen levels at study inclusion (Imunbind total TFPI ELISA kit, American Diagnostica Inc., USA) were measured in patients included in the Vienna Cancer and Thrombosis Study (CATS), which is a prospective observational cohort study including patients with newly diagnosed or recurrent cancer. Patients were followed for objectively diagnosed, independently adjudicated VTE for up to 2 years. The association between TFPI-levels and VTE-risk was analyzed in competing risk analysis, considering death as competing outcome event. The association of TFPI-levels with all-cause mortality was assessed in Cox regression analysis.

Results TFPI was analyzed in 898 patients (median age 62 years, interquartile range [IQR]: 53-68; 407 (45%) female). Over a median follow-up time of 22 months (IQR: 7-25), 67 patients were diagnosed with VTE and 387 patients died (6-, 12-, and 24-month cumulative risk: 5.5%, 6.7%, 7.5% and 15.1%, 27%, 42.1%).

Patients had median TFPI levels of 56.4 ng/mL (IQR: 45-70). Distribution of TFPI levels did not significantly differ between cancer types. Patients with metastatic vs non-metastatic disease had higher TFPI levels (median: 60 vs 50.4 ng/mL, p<0.001).

In multivariable analysis adjusting for age, sex, cancer type and stage, baseline levels of TFPI were associated with risk of VTE (SHR per doubling: 2.01, 95% confidence interval [CI]: 1.25-3.24; 1-year cumulative incidence >75th vs ≤75th percentile: 9.7 vs 5.8, p=0.04, [Fig. 1]). Further, TFPI was independently associated with risk of all-cause mortality (adjusted HR per doubling: 1.86, 95%CI: 1.47-2.35; 1-year cumulative incidence >75th vs ≤75th percentile: 47.2 vs 21.7, p<0.001, [Fig. 2]).

Fig. 1  Cumulative VTE Incidence of patients (n=898) with TFPI levels ≤75th (n=680) (≤70 ng/mL) versus >75^th percentile (n=218) (>70ng/mL). Patients were divided according to their TFPI level and the group with levels under 70 ng/mL (≤75th percentile) was compared to the group with levels over 70 ng/mL (>75th percentile) within a Fine and Gray subdistribution hazard model, p=0.04

Fig. 2  Overall-survival of patients (n=898) with TFPI levels ≤75th (n=680) (≤70 ng/mL) versus >75th percentile (n=218) (>70 ng/mL). Patients were divided according to their TFPI level and the group with levels under 70 ng/mL (≤75th percentile) was compared to the group with levels over 70 ng/mL (>75th percentile) within a Kaplan Meier analysis and with a log-rank test p<0.001

Conclusion TFPI levels are independently associated with risk of VTE and all-cause mortality in patients with cancer. Interestingly, patients with metastatic disease had higher TFPI levels. TFPI levels might represent a surrogate and could be a biomarker for the prediction of VTE risk and mortality in patients with cancer.

Conflict of Interest

No conflicts of interest to disclose.

Publication History

Article published online:
20 February 2023