VTE risk

Cancer-associated thrombosis (CAT) is a common cause of death amongst the cancer population. The increased risk of recurrent venous thromboembolism (VTE) and bleeding complications in patients with cancer makes anticoagulant treatment and management of VTE challenging¹. Listen to Professor Agnelli, from the University of Perugia, to find out the challenges of treating CAT?

Virchow's triad of hypercoagulability, venous stasis, venous thrombosis and endothelial damage provides a model for understanding many of the risk factors that lead to the formation of the disease (Figure 1)^2,3. CAT is characterised by either deep vein thrombosis (DVT), pulmonary embolism (PE), superficial vein thrombosis, and splanchnic vein thrombosis. Malignancy is often associated with VTE, because of the hypercoagulable state induced by malignancy⁴.

Figure 1. Risk factors for venous thromboembolism (adapted from Phillipe HM, 2017⁵).

Rudolph Virchow first proposed a triad of causes, Virchow’s triad, which lead to venous thrombosis: venous stasis, blood hypercoagulability, and vascular wall injury. Venous stasis may be a product of immobility. Several haematologic abnormalities of coagulation factors or natural anticoagulants increase blood hypercoagulability and thrombotic risk. Vascular wall injury promotes circulation of coagulation enzymes and cofactors. In addition to advanced age, all these components influence current known risk factors for VTE.

It is estimated that the annual incidence of VTE in patients with cancer is five times greater than in the general population (0.5% versus 0.1%, respectively)⁶. Active cancer accounts for 20% of the overall incidence of the disease⁷. Let’s take a more in-depth look at the prevalence of CAT, which is the second leading cause of death in patients suffering from malignant tumours, after death from cancer itself⁸.

It is estimated that the annual incidence of VTE in patients with cancer is five times greater than in the general population⁶.

Data from the Framingham Heart Study demonstrated that in a prospective cohort of 9,754 patients, CAT had worse survival among VTE patients⁹. Similarly, data from the Global Anticoagulant Registry in the Field (GARFIELD)-VTE registry demonstrated that in a cohort of 10, 315 patients, from 419 centres and 28 countries, overall mortality was 9.7% after 6 months and 54.3% of all deaths were cancer-related⁸.

Studies are being conducted to investigate the efficacy and safety of new treatments for cancer related VTE including trials involving direct oral anticoagulants (DOACs) and low molecular weight heparin (LMWH)¹⁰.

The pathophysiology of VTE includes general and biological risk factors, common to cancer and non-cancer patients, however in patients with malignancy there are an additional number of disease-specific factors, which render the pathogenesis unique¹¹.

The thrombotic generation process in the cancer patient is distinct from the non-cancer population. Multiple clinical factors together with biological pro-coagulant mechanisms expressed by cancer tissues are involved in the activation of blood coagulation and importantly contribute to the overall thrombotic risk of DVT and PE of patients with cancer (Figure 2)^11,12.

Figure 2. Pathogenesis of thrombophilic state in cancer patients (adapted from Falanga et al, 2019¹⁰). VTE, venous thromboembolism.

Altogether, these factors favour a shift in the haemostatic balance toward VTE, as indicated by the appearance of subclinical coagulation changes in almost all patients with cancer, who often present with high risk levels of circulating biomarkers of hypercoagulability such as tissue factor, cancer pro-coagulant, D-dimer and microparticles^11,12.

Several mechanisms have been proposed for pathogenesis of the hypercoagulable state, such as tumour production of tissue factor‑like pro-coagulant and cancer pro-coagulant (a calcium‑dependent cysteine protease), alongside with pro-coagulant activities expressed by host tissues (P‑selectin found in platelet granules and in Weibel‑Palade bodies of endothelial cells, tissue factor produced by monocytes, increased platelet activation secondary to amplified production of thrombin, neoplastic cell adenosine diphosphate [ADP] production and high levels of von Willebrand factor, neutrophil extracellular traps)⁴.

A protein that is considered critical to CAT is tissue factor, which plays a role both in oncologic progression and in VTE formation. It is abnormally produced by cancer cells and is an activator of the extrinsic coagulation pathway resulting in the activation of factor X and consequently in fibrin synthesis and platelet activation⁸.

Besides tissue factor, some cancer cells can also produce other substances, such as distinct cancer pro-coagulant factors that directly stimulate factor Xa. Additionally, there are inflammatory cytokines that mediate endothelial dysfunction, and hence blood flow, as well as other substances produced by tumours, such as carcinoma mucins, that also interfere in the coagulation cascade. The fibrinolytic system is also inhibited by the cancer cell synthesised plasminogen activator inhibitor-1. This imbalance in the pro-anticoagulation state leads to generation of VTE⁸.

Arterial Thrombosis

Although there is less data available on arterial thrombosis in cancer compared with VTE it is nonetheless observed in cancer. There have been multiple case reports suggesting acute arterial thrombosis in the setting of a new malignancy¹³. Let’s find out more by listening to Professor Agnelli discuss the association between arterial thrombotic events and malignancy.

The incidence of VTE increases exponentially with the increase in presented risk factors. A thorough risk score system and risk stratification is essential to help physicians plan particular prophylactic approaches for patients prone to develop the disease¹⁴. Hear our expert Professor Agnelli discuss the risk factors for CAT, the importance of risk stratification and the risk stratification tools that are available.

At least one VTE risk factor is present in most critically ill patients who have sought medical attention, and usually the risk of the disease remains for several weeks after discharge from hospital¹⁵. Risk stratification tools, in addition to VTE in cancer guidelines, may help to reduce the number requiring long term treatment by guiding selection of cancer patients at high risk. An ideal risk score, which would supplement guidelines for VTE in cancer patients, would help clinicians identify patients at very high risk of developing VTE¹⁶. Let’s find out more about how physicians stratify patients based on risk?

Ottawa score, Khorana score, and Caprini VTE risk assessment are the three most common and valuable predictive scoring systems for VTE in cancer populations¹⁴. Of those three, the best-known risk stratification tool is the Khorana score, which was introduced in 2008¹⁶.

The Khorana score is endorsed by the latest guideline updates of the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) to select ambulatory cancer patients for thromboprophylaxis¹⁶.

The Khorana score assigns points to five clinical and pre-chemotherapy laboratory parameters: primary tumour site (+1 or 2 points), platelet count ≥350x10⁹/L (+1 point), haemoglobin concentration ≤100 g/L or use of erythropoiesis-stimulating agents (+1 point), leukocyte count ≥11x10⁹/L (+1 point), and a Body Mass Index (BMI) ≥35 kg/m² (+1 point). A sum score of 0 points classifies patients as being at low risk of VTE, 1 or 2 points at intermediate risk, and those with ≥3 points at high risk (Table 1)¹⁶.

Table 1.  Parameters of the Khorana risk score (adapted from Mulder et al, 2019¹⁶).

The Khorana score is endorsed by the latest guideline updates of the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) to select ambulatory cancer patients for thromboprophylaxis¹⁶. Based on preliminary results, the use of the Khorana score at a cutoff ≥3 was initially proposed in a thromboprophylaxis guidance statement. However, later studies disclosed its low sensitivity for certain tumour types, such as lung or pancreatic cancer. Moreover, the high proportion of patients (>50%) falling into the intermediate risk category represented a serious drawback. In fact, while the decision to treat low risk or high risk patients is fairly easy, how to handle patients in the intermediate risk category represents a big challenge for physicians. Thus, recent randomised trials have adopted the use of a cut off ≥2 to stratify cancer patient candidates suitable for thromboprophylaxis¹².

Interim results from the CASSINI study demonstrated that rivaroxaban (a highly selective direct factor Xa inhibitor) significantly reduced VTE and VTE-related death during the on-treatment period in at risk ambulatory cancer patients selected on the basis of a Khorana score ≥2. The same selection criteria were used in the AVERT study, whose results suggest that apixaban (another highly selective direct factor Xa inhibitor) significantly lowers the incidence of VTE in intermediate to high risk ambulatory cancer patients starting chemotherapy, although at a higher rate of major bleeding compared to placebo^12,17,18.

The feasibility of a revised cut off at ≥2 points was recently confirmed in a meta-analysis specifically designed to estimate the performance of the Khorana score. Using a threshold of 2 points rather than the conventional 3 points, a substantial increase in the proportion of high-risk patients (from 17% to 47%) was observed, paralleled by a reduction in absolute VTE risk (from 11% to 9%). In real-world clinical practice however, the Khorana risk score was shown to have no influence on the therapeutic decision to start prophylaxis in the CAT AXIS, a multicentered cross-sectional case vignette study on clinical practice in France^,12,19.

Other scores have attempted to increase the Khorana score’s predictive performance by introducing different variables, such as soluble biomarkers (as in the Vienna Cancer and Thrombosis Study-CATS-score), clinical features (as in the CONKO score, specifically developed for lung cancer), or the use of specific chemotherapy regimens (as in the PROTECHT score)¹².

Automated predictive models for VTE risk prediction and stratification represent innovative clinical decision support systems that are experiencing a significant boost thanks to the rapid progress of tools allowing the development of customised interfaces extracting data from electronic health records. Customised and evidence-based management of patients could provide a real-time VTE risk calculation guiding clinicians in the decision making process¹².

Cancer-Associated VTE Guidelines

References

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