Written by Lucy Norris PhD.
Coagulation research laboratory, Dept of Obstetrics and Gynaecology, Trinity St. James’s Cancer Institute, Trinity Centre for Health Sciences, St. James Hospital, Dublin 8
Cancer associated venous thromboembolism
Venous thromboembolism (VTE) is a potentially lethal complication of cancer and is the leading cause of death in cancer patients after the cancer itself. Cancer associated VTE increases morbidity and can impact patient’s quality of life, frequently resulting in delays or interruptions in cancer treatment. Despite advances in preventative treatment, the rate of cancer associated VTE has risen substantially in the last 20 years particularly in patients receiving chemotherapy. Up to 20% of patients will experience VTE during their cancer journey and the risk of VTE in cancer patients is 4-7-fold higher than in the general population. Patient, tumour, and treatment factors all contribute to the risk of VTE in cancer. Tumour site is a major determinant of VTE risk; pancreatic, brain, ovarian and lung cancer are associated with the highest VTE rates. The risk of VTE in cancer patients is increasing in tandem with the rising rate of cancer worldwide and the increased survival of cancer patients.
Cancer treatments are a significant contributor to VTE risk, in particular cancer surgery with resulting immobility and hospital stay. Chemotherapy is also a major contributor to VTE risk. The effects of chemotherapy and surgery can be additive. Ovarian cancer patients who cannot be optimally debulked 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 have reported VTE rates as high as 27%.
Emerging evidence suggests that newer targeted cancer therapies are also prothrombotic. Immune checkpoint inhibitors, frequently used in lung cancer, are associated with an increased risk of both venous and arterial thrombotic events, particularly in those tumours with specific molecular profiles eg ALK-/ROS-translocations in non small cell lung cancer. It is unclear however whether these events are linked to the biology of the underlying cancer or are due to a mechanistic effect of the therapy.
Pathogenesis of VTE in cancer
The pathogenesis of VTE was described by Virchow in the middle of the 19th century as a triad of venous stasis, hypercoagulability and endothelial damage which interact to promote the development of a thrombus (Figure 1). In a cancer patient, all three components of the Virchow’s triad are present. A bulky tumour can lead to venous compression and venous stasis, tumours express procoagulant material which, when released into the circulation, can trigger activation of the coagulation cascade. Damage to the vascular endothelium due to chemotherapy or surgery creates a procoagulant surface for the developing thrombus.
Figure 1. Virchow’s Triad
Cancer is now recognised as a pro-inflammatory condition. Reports suggest that tumours express pro-inflammatory cytokines which interact with the coagulation pathway (Figure 2). Obesity, a risk factor for many cancers, has been associated with a state of low-grade systemic inflammation. This is characterized by an adipose tissue driven acute-phase response resulting in secretion of cytokines.
Figure 2: Pathogenesis of VTE in cancer patients
VTE risk assessment in cancer- the importance of biomarkers
Although VTE is a significant cause of morbidity and mortality in the general population, effective anticoagulant treatments are available for treatment and prevention of this disease. However VTE in cancer patients represents a significant clinical problem, since these patients have higher rates of both bleeding and VTE recurrence compared with the non-cancer population. This highlights the need for a careful risk/benefit assessment of prophylaxis.
Patients are particularly at risk of VTE following cancer surgery. As a result, international guidelines recommend extended (28 day) prophylaxis with Low Molecular Weight Heparin(LMWH) for all patients having major pelvic/abdominal cancer surgery. However, VTE still occurs in a significant number of patients post-surgery despite extended LMWH prophylaxis which suggests that the dose of LMWH or duration of prophylaxis may be inadequate in these patients. In contrast, recent advances in minimally invasive surgery (MIS) have led to questions regarding the benefits of extended prophylaxis in lower risk women undergoing MIS. VTE rates following MIS in cancer patients are reported to be low and many investigators feel that extended prophylaxis is neither warranted or beneficial in these patients. Current recommended risk assessment methods for surgical patients (Caprini score) have limited sensitivity in cancer patients and are seldom used in practice.
In patients undergoing chemotherapy, recent guidelines have suggested that primary VTE prophylaxis with direct oral anticoagulants (DOACs) should be considered for intermediate/high risk ambulatory cancer patients following risk assessment. However, in practice uptake is low, even in high risk patients, due largely to concerns over reported bleeding risks associated with DOACS.
The recommended tool for VTE risk assessment during chemotherapy is the Khorana score, a risk model based on five easily available clinical parameters which has been extensively validated in mixed cancer studies. However, the Khorana score performs poorly in in some patient groups including those at high risk of thrombosis such as lung and ovarian cancer. The guidelines recommend a single assessment prior to treatment but 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. For optimal VTE prophylaxis in the cancer patients, ongoing VTE risk assessment is required.
Biomarkers for pro-coagulant activity offer the opportunity for serial assessment of cancer patients This approach offers a more tailored approach to prophylaxis, minimising the risk of bleeding complications. Research by our group and others has identified several biomarkers which can be used alone or in combination with clinical variables for prediction of VTE in cancer patients.
Biomarkers for prediction of VTE in cancer
D-dimer is the fragment produced when fibrin is cleaved and thus represents fibrin turnover and coagulation activation. D-dimer is widely used a diagnostic biomarker of VTE, although highly sensitive and easily measured in the hospital laboratory, the specificity of D-dimer is reduced in many conditions including infection, surgery, and cardiovascular disease. D-dimer has been identified as the strongest prognostic biomarker for VTE in patients with cancer. In the Vienna CAT score, a nomogram combining cancer site with D-dimer levels was used to predict VTE in a mixed cancer population. In lung cancer and in pancreatic cancer pre-treatment levels have been used to predict VTE in patients undergoing chemotherapy. However due to the low specificity of D-dimer, the positive predictability of this biomarker is low. In ovarian cancer D-dimer is used to triage patients and high levels are an indicator of advanced disease rather than VTE risk. Several groups have attempted to dynamically assess D-dimer levels as a marker for VTE during chemotherapy with limited success due to the variability of D-dimer during treatment and the difficulty of selecting appropriate cut-offs to account for comorbidities.
Global markers of hypercoagulability are attractive candidates as predictors of VTE as they capture the composite effects of activators and inhibitors of the haemostatic system which drive thrombus formation. The thrombin generation assay quantifies the enzymatic thrombin activity that can be triggered in plasma. Measurement of thrombin generation has a positive predictive value independent of D-Dimer. Recent developments have transformed the thrombin generation assay into a high throughput assay suitable for clinical use however there are still issues with variability and thrombin generation has yet to gain widespread acceptance in the clinic.
We and others have shown that thrombin generation is increased in patients who subsequently develop cancer associated VTE and can be used as a predictive biomarker. Our group has developed the Thrombogyn score, a risk score developed from clinical risk factors for prediction of VTE in gynaecological cancer patients post surgery. We extended the Thrombogyn score with the addition of two biomarkers Thrombin generation (ETP) and D-dimer, which were measured pre-operatively. Using this extended Thrombogyn score, a high risk group was identified of which, 42% of patients developed VTE. The extended score had a sensitivity of 95.7% compared with 72% for the score without biomarker data. The Khorana score has a sensitivity of 35-50% for high risk patients.
Further work by our group has identified the key determinants of the increased thrombin generation in cancer patients who develop VTE. In both treatment naïve and neoadjuvant treated gynaecological cancer patients, factor VIIIc was increased in patients who subsequently developed VTE compared with those who remained thrombosis free. Raised factor VIIIc levels were associated with 2.8 fold increase in VTE adjusted for age, stage of cancer and chemotherapy. This is in agreement with several groups who have shown that Factor VIIIc can predict VTE in a mixed group of cancer patients.
Thrombomodulin and the activated protein C pathway
The protein C pathway is a major regulator of thrombin production. Binding of thrombin to thrombomodulin(TM) on the endothelial cell surface leads to the activation of protein C(aPC) which is accelerated by the endothelial protein C receptor(EPCR) (Figure 3).
Figure 3. Activation of protein C
Endothelial damage resulting in reduced expression of TM on the endothelial surface can cause a reduction in the activation of protein C. Failure of protein C activation or resistance to the inhibitory effects of aPC (both genetic and acquired) is a common cause of VTE. Our recent data has shown that chemotherapy alters the aPC pathway. We observed reduced soluble TM in patients who developed VTE following neoadjuvant chemotherapy suggesting that reduced generation of aPC may be implicated in chemotherapy associated VTE. TM levels were inversely correlated with thrombin generation suggesting a direct relationship between TM and thrombus formation in cancer associated VTE. These changes do not occur in similar patients who are treatment naïve suggesting that this is a treatment effect.
In vivo and in vitro data published by our group has shown that platelets play a role in metastasis, forming a so called “platelet cloak” around tumour cells as they escape from the primary tumour into the circulation. This allows them to evade natural defence mechanisms in the body and is linked to poor prognosis. The adhesion molecule P-selectin, is expressed on the platelet membrane following platelet activation. s-P- Selectin is cleaved and shed in the circulation and has been reported as a marker of VTE in cancer patients. This underlines the role that platelets have not only in metastasis but also in cancer associated VTE. Recent studies have shown that the mechanisms by which p-selectin mediates cancer associated VTE are linked to cancer associated inflammation and metastasis. P-selectin has been shown to be an independent predictor of VTE and, along with factor VIII and D-dimer, was elevated longitudinally in a small cohort of cancer patients sampled serially prior to the development of VTE.
New approaches to biomarker discovery.
Our research and those of many groups has focussed on investigating procoagulant biomarkers for VTE in circulating blood. With the availability of multiplex assays and arrays, several hundred potential biomarkers can be investigated from a small sample. Using this approach, candidate biomarkers unrelated to coagulation such as stromal cell–derived factor-1 (SDF-1), thyroid-stimulating hormone (TSH), and monocyte chemotactic protein 4 and growth hormone (GH) and interleukin-1 receptor type 1 (IL-1R1) have recently been identified. The mechanism by which these cytokines and hormones induce thrombus formation is not understood and prospective longitudinal analysis will determine their future role in VTE risk prediction. At a molecular level, tumour expressed microRNAs have been shown to be predictive of VTE in colorectal cancer. In glioblastoma, targeted next generation sequencing has been used to identify tumour mutations associated with VTE.
Cancer associated VTE is a significant medical problem which persists throughout the course of the disease. Effective and safe prevention of VTE is required particularly in the era of evolving targeted therapies with unknown thrombotic potential. Current risk models do not provide the sensitivity to accurately identify patients who will most benefit from prophylaxis. Serial measurement of biomarkers used alone, or in combination with clinical risk factors can increase the sensitivity of risk prediction and allow personalised treatment so that the right patient gets prophylaxis at the right time. Longitudinal studies are required to identify the most effective combinations for dynamic assessment of VTE risk.
References available on request
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