Mechanisms of coagulation disturbances in cancer
Even in the absence of clinical manifestations of thrombosis, cancer patients commonly present with a subclinical hypercoagulable condition, characterized by varying degrees of clotting activation.1 Cancer patients frequently demonstrate abnormalities in each component of Virchow’s triad, resulting in a prothrombotic state. Blood flow stasis is due to vascular compression by solid tumours, hyper-viscosity, or immobilization, while endothelial lesions result from anticancer therapy, secondary to direct invasion by tumour or to increased circulating cytokine levels. Many mechanisms lead to hypercoagulability in cancer, but the main role is played by the tumour cells, which express procoagulants such as TF (tissue factor), CP (cancer procoagulant), factor V receptor, fibrinolytic proteins or receptors, and MP (microparticles). Cancer cells are able to interact with host cells and to activate their procoagulant potential by releasing soluble mediators and by expressing adhesion molecules.2
The link between haemostasis and tumour growth
Malignancy and haemostasis are intimately correlated. First, malignancy promotes a hypercoagulable state and second, the activated haemostatic machinery has an important contribution to tumour growth, invasion, and neo-angiogenesis.
Tumour cells can express on their surface different molecules of the fibrinolytic pathway. As a contributor to cancer progression, fibrinolysis is activated when uPA (urokinase-type plasminogen activator) binds to its receptor expressed on tumour cells, resulting in plasmin formation, which cleaves the fibrin network in clots, but also the extracellular matrix, allowing the invasion of tumour cells in the surrounding tissues.3
The primary haemostatic system is also involved in cancer growth and dissemination, as tumour cells express surface receptors for binding to vWF (von Willebrand factor) and to platelets.vWF enables tumour cells to bind to the endothelial surface where they release cytokines, resulting in increased vascular permeability that facilitates their dissemination in the surrounding tissue.
In the circulation, cancer cells can activate platelets leading totumour cell-induced platelet aggregation (TCIPA) and to the coverage of the tumour cells by a platelet layer that protects them from destruction by immunological attack.3
Physiologic angiogenesis is closely related to haemostasis. Growing tumours need to develop adequate vasculature to meet their metabolic needs. By activating the coagulation system, tumour cells induce the production of proangiogenic factors and decrease the release of antiangiogenic factors, leading to the formation of a fibrin matrix where the new blood vessels develop.3
Clinical expression of coagulopathy in cancer patients
Even if all types of thrombotic events such as venous and arterial thrombosis, or disseminated intravascular coagulation (DIC) are described in cancer patients, venous thromboembolic events (VTE) are the most well-studied. The thrombotic risk of cancer patients depends on general cardiovascular risk factors, cancer-specific risk factors, and anti-cancer therapies.
The incidence of VTE in cancer is 4-7 times higher than in the general population, variable depending on the type and extent of cancer.2Patients with pancreas, stomach, or brain cancers or with metastatic disease have the highest rate of VTE.Cancer patients with VTE have an increased risk of recurrence and of major bleeding during anticoagulant therapy compared to non-cancer VTE patients, and a worse outcome compared to cancer patients without VTE. Primary VTE prophylaxis is recommended in hospitalized cancer patients and in high-risk cancer outpatients such as patients with Khorana Score ≥3 or advanced pancreas cancer receiving chemotherapy.4For the treatment and secondary prevention of VTE in cancer, the use of LMWH (low molecular weight heparin) reduces the risk of recurrence at 6 months compared to VKAs (vitamin K antagonists), while the use of DOACs (direct anticoagulants) compared with LMWH results in decreased VTE recurrence, but increased bleeding risk. Current recommendations for acute VTE in cancer include DOACs in the case of low bleeding risk patients and LMWH for patients with cancers at risk of bleeding.5
The incidence of arterial thrombosis (ATE) in cancer is lower compared to VTE. The highest risk of ATE is found in lung and kidney cancer, while breast cancer has the lowest risk. The occurrence of ATE is associated with a 3-fold increased risk of mortality in cancer patients.6While primary prevention of ATE in cancer is not currently recommended, the use of antiplatelet agents and revascularization therapy for treatment and secondary prevention is complicated by thrombocytopenia and by the increased risk of stent thrombosis and impaired endothelialisation associated with chemotherapy, respectively.
Haemostasis in cancer-assessment and potential therapeutic target
The usefulness of different thrombotic and fibrinolytic biomarkers for the early diagnosis of cancer patients, for predicting the patient prognosis or the occurrence of thrombotic events before starting anticancer treatments, and for selecting a high-risk subset of patients that may benefit from antithrombotic therapy is currently being investigated. However, as the number of haemostatic markers is very large, it is challenging to put together all the results to get the whole picture of the haemostatic balance in cancer patients; for this purpose, more global haemostatic tests might be useful. Visco-elastic tests and thrombin generation tests (TGT) reveal cancer-associated hypercoagulability, while TGT could be useful to identify cancer patients with high thrombotic risk.7
Anticoagulant or antiplatelet therapy in cancer patients without VTE or ATE was associated in some studies with improved survival, although this has not been consistent across all studies.8,9 Current research investigates new therapeutic approaches involving antithrombotic drugs or targeting specific haemostatic pathways to address cancer-induced haemostatic imbalance leading to thrombotic complications and to cancer progression.
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- Falanga A, Russo L, Milesi V, et al. Crit Rev Oncol Hematol2017;118:79-83.
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- Khorana AA, Carrier M, Garcia DA, et al. J Thromb Thrombolysis2016;41(1):81-91.
- Khorana AA, Noble S, Lee AYY, et al. J Thromb Haemost2018;16(9):1891-4.
- Grilz E, Konigsbrugge O, Posch F, et al. Haematologica2018;103(9):1549-56.
- Ay C, Dunkler D, Simanek R, et al.J Clin Oncol2011;29(15):2099-103.
- Sanford D, Naidu A, Alizadeh N, et al. J Thromb Haemost2014;12(7):1076-85.
- Rothwell PM, Wilson M, Price JF, et al. Lancet2012;379(9826):1591-601.