Abstract
The high occurrence of cancer-associated thrombosis is associated with elevated thrombin generation. Tumour cells increase the potential for thrombin generation both directly, through the expression and release of procoagulant factors, and indirectly, through signals that activate other cell types (including platelets, leukocytes and erythrocytes). Furthermore, cancer treatments can worsen these effects. Coagulation factors, including tissue factor, and inhibitors of coagulation are altered and extracellular vesicles (EVs), which can promote and support thrombin generation, are released by tumour and other cells. Some phosphatidylserine-expressing platelet subsets and platelet-derived EVs provide the surface required for the assembly of coagulation factors essential for thrombin generation in vivo. This review will explore the causes of increased thrombin production in cancer, and the availability and utility of tests and biomarkers. Increased thrombin production not only increases blood coagulation, but also promotes tumour growth and metastasis and as a consequence, thrombin and its contributors present opportunities for treatment of cancer-associated thrombosis and cancer itself.
Highlights
Patients with cancer are at high risk of pathological thrombosis with risk often exacerbated during cancer treatments
When it comes to clinical samples, the evidence for and against the contribution of tissue factor (TF)+extracellular vesicles (EVs) to increased thrombin generation in cancer thrombosis is more heterogeneous and mostly does not distinguish between tumour-specific EVs and EVs released by other cell types
Studies in the pathogenesis of cancer indicate a key role for thrombin in tumour progression, no single assay has been able to predict risk of thrombosis and outcome in all cancers, pointing to the complexity and multi-factorial nature of this phenomenon
Summary
Patients with cancer are at high risk of pathological thrombosis with risk often exacerbated during cancer treatments. The implications of elevated levels of thrombin are far-reaching, as this indicates a hypercoagulable state and resultant increased risk of cancer-associated thrombosis [5,8] and promotion of tumour growth and metastasis (reviewed in [9,10,11]). Many factors, both circulating and tumour-direct, contribute to this increased thrombin generation (Figure 1). Thrombin Generation Requires Activation of the Coagulation System and Membrane
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