Tissue Factor Pathway Inhibitor 2: A Novel Biomarker for Predicting Asymptomatic Venous Thromboembolism in Patients with Epithelial Ovarian Cancer

Abstract

<b><i>Objectives:</i></b> Patients with asymptomatic venous thromboembolism (VTE) are associated with an increased risk of pulmonary thromboembolism events. However, due to low specificity and high false-positive rates, D-dimer testing cannot be used alone to diagnose VTE. Tissue factor pathway inhibitor 2 (TFPI2), a new serodiagnostic marker for ovarian cancer, plays a role in blood coagulation system regulation. We hypothesized that combining D-dimer and TFPI2 would improve its utility in diagnosing VTE. This study aimed to look into the clinical utility of serum D-dimer and TFPI2 levels in detecting asymptomatic VTE in patients with epithelial ovarian cancer (EOC). <b><i>Design:</i></b> From January 2008 to December 2015, researchers at Nara Medical University Hospital’s Department of Gynecology conducted a single-center retrospective study. The receiver operating characteristic (ROC) curve analysis was used to determine the diagnostic value of preoperative D-dimer, TFPI2, and D-dimer combined with TFPI2 in distinguishing VTE patients from those who did not have VTE. <b><i>Participants:</i></b> This study included 122 patients with EOC who met the inclusion and exclusion criteria out of 223 admitted to the hospital with EOC. The patients were divided into two groups: VTE (<i>n</i> = 25) and non-VTE (<i>n</i> = 97). <b><i>Results:</i></b> There were significant differences in D-dimer, TFPI2, and CA125 levels and residual tumor between the VTE and non-VTE groups. The D-dimer level was found to be significantly related to age, body mass index, VTE, massive ascites, residual tumor, histology, and Federation of Gynecology and Obstetrics stage, whereas the TFPI2 level was only related to VTE. Multivariate analysis revealed that D-dimer (the optimal cutoff value, 3.5 μg/mL) and TFPI2 (the optimal cutoff value, 400 pg/mL) are independent risk factors for preoperative VTE. ROC analysis revealed that the area under the curve was 0.8266 for D-dimer, 0.7963 for TFPI2, and 0.8495 for the combination of D-dimer and TFPI2. When compared to the D-dimer test alone, the combination of D-dimer and TFPI2 had higher specificity (77.3–96.9%) and positive predictive value (48.8–81.2%) for the diagnosis of VTE. <b><i>Limitations:</i></b> This is a single-center retrospective study. <b><i>Conclusion:</i></b> The combination of D-dimer and TFPI2 may be useful to safely exclude VTE and select patients at high risk of VTE.

Tissue Factor Pathway Inhibitors as Potential Targets for Understanding the Pathophysiology of Preeclampsia

“…A multicenter prospective cohort study revealed that TFPI2 is a novel serum biomarker for predicting ovarian cancer [9]. Furthermore, ovarian cancer patients who experienced VTE had elevated TFPI2 levels compared to those without thromboembolic events, suggesting that TFPI2 may be a biologic marker for predicting VTE [15,16]. A better understanding of the biological functions of TFPI2 may help develop optimal therapeutic strategies not only for cancer and VTE, but also for preeclampsia.…”

“…Third, there is clinical evidence that TFPI2 contributes to promoting the thrombus formation. Indeed, in patients with ovarian cancer, elevated serum TFPI2 levels were reported to be associated with an increased risk of VTE [15,16]. A multivariate analysis showed that a cut-off value of 12.5 pM for TFPI2 was an independent risk factor for VTE.…”

“…Furthermore, two TFPI1 isoforms, TFPIα and TFPIβ, are generated by alternative mRNA splicing [14]. Recent studies have shown that decreased TFPI1 [11] levels or increased TFPI2 [15,16] levels are associated with an increased risk of thromboembolism in cancer patients, suggesting that TFPI1 and TFPI2 may exhibit different biological activities. On the other hand, a number of studies have shown that not only TF, but also TFPI1 and TFPI2 are elevated, to varying degrees, in preeclamptic patients [17][18][19][20].…”

The Endometriotic Neoplasm Algorithm for Risk Assessment (e-NARA) Index Sheds Light on the Discrimination of Endometriosis-Associated Ovarian Cancer from Ovarian Endometrioma

“…To overcome this bias, a multi-center prospective cohort study is now proceeding (UMIN000034969). Second, the newly reported tumor marker of tissue factor pathway inhibitor 2 (TFPI2) was not assessed [ 74 , 75 ]. Finally, we did not compare diagnostic efficacy among the IOTA classification, ROMA index, the CPH index, and the e-NARA index.…”

The role of tissue factor pathway inhibitor 2 in the coagulation and fibrinolysis system

“…Surprisingly, TFPI2 was significantly elevated in ovarian cancer patients with VTE compared with non-VTE patients, suggesting that it is actually associated with VTE risk. 11,12 In addition, elevated serum TFPI2 levels have also been reported in patients with preeclampsia [13][14][15] and atherosclerosis. 16 Since TFPI2 inhibits the TF-mediated coagulation pathway, we initially thought that, like TFPI1, elevated TFPI2 would suppress thrombus formation.…”