A novel biomarker for chemotherapy-associated venous thromboembolism

Ovarian cancer patients are at high risk of venous thromboembolism (VTE). More than 80% of women present with a metastatic disease that contributes to the high rate of VTE [1]. The cornerstone of ovarian cancer treatment is cytoreductive surgery followed by adjuvant chemotherapy. However, patients who cannot undergo optimal debulking are frequently treated with neoadjuvant platinum-based chemotherapy followed by interval debulking surgery, which further exacerbates VTE risk. Recent studies of patients with ovarian cancer receiving neoadjuvant chemotherapy (NACT) have reported VTE rates as high as 27% [2]. Endothelial damage, inflammation as well as tumor-associated procoagulant activity may all contribute to the increased risk [3]. A recent report has shown that a key natural anticoagulant pathway, the activated Protein C pathway (aPC), is dysregulated during chemotherapy resulting in a procoagulant phenotype [4].

Risk assessment during chemotherapy – why biomarkers are important

Primary VTE prophylaxis with direct oral anticoagulants (DOACs) has been recommended for intermediate/high-risk ambulatory cancer patients undergoing chemotherapy. However, uptake is low, even in high-risk patients, largely because of concerns over reported bleeding risks associated with DOACs and the lack of reliable risk assessment tools. The most widely used and extensively validated tool for VTE risk assessment in cancer is the Khorana score [5]. Nevertheless, the Khorana score performs poorly in some patient groups, including those at high risk of thrombosis, such as in the lung or ovarian cancer [6].

The interplay between cancer, coagulation activation, and chemotherapy is a dynamic process and is unlikely to be accurately represented by a single risk assessment at the start of therapy. Another approach to risk assessment has been the adoption of biomarkers of pro-coagulant activity used alone or in combination with clinical risk factors [3]. This approach has been used successfully to predict VTE in gynecological cancer patients post-surgery [7].

D-dimer has been identified as the strongest prognostic biomarker for VTE in patients with cancer [8]. However, D-dimer is frequently raised in ovarian cancer and has been proposed as a useful diagnostic marker for triaging patients; therefore, the specificity of D-dimer as a biomarker for VTE in ovarian cancer is low.

The aPC pathway in cancer-associated VTE

Studies on coagulation markers in cancer have focused on coagulation activation markers in mixed populations of both treated and untreated cancer patients. Few studies have investigated the effect of chemotherapy on the key regulatory pathways controlling thrombin and fibrin generation. Exposure of vascular endothelial cells to common chemotherapeutic agents can alter anticoagulant activity with the loss of a thromboresistant phenotype.

The protein C pathway is a major regulator of thrombin production. The binding of thrombin to thrombomodulin (TM) on the endothelial cell surface leads to the activation of protein C, which is accelerated by the endothelial protein C receptor (EPCR) [9]. TM is crucial in protein C activation and acts by tethering thrombin to the endothelial surface, facilitating thrombin-mediated protein C activation. Endothelial damage resulting in reduced expression of TM on the endothelial surface can cause a reduction in protein C activation. Failure of protein C activation or resistance to the inhibitory effects of activated protein C (both genetic and acquired) is a common cause of VTE [9].

Thrombomodulin as a biomarker for chemotherapy-associated VTE?

Recent data has shown that soluble TM is reduced in patients undergoing neoadjuvant chemotherapy who subsequently develop VTE. In addition, TM levels in these patients are inversely correlated with thrombin generation, suggesting a direct relationship between TM and thrombus formation in cancer-associated VTE [10].

In support of this, increased resistance to aPC was also observed as determined by the TM-modified ETP assay. Regression analysis showed that patients with TM levels below the cut-off had a 4-fold increased risk of VTE following interval debulking surgery despite extended LMWH prophylaxis [10]. These changes are specific to patients who have undergone neoadjuvant chemotherapy and do not occur in similar patients who are treatment naïve. This suggests that this effect is due to treatment rather than cancer itself.

Conclusions

Lower levels of TM may cause a reduced activation of protein C associated with a prothrombotic phenotype resulting in VTE in patients who have undergone chemotherapy treatment. Serial determination of TM levels may serve as a novel dynamic predictive biomarker for VTE during chemotherapy in cancer patients. It may also be a useful tool for selecting high-risk patients for primary VTE prophylaxis during chemotherapy.

References

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