Blood clot generation in people with cancer follows a process distinct from the non-cancer population.
Cancer tissue is in a state of inflammation and hypoxia and produces a series of substances that contribute to the formation of thrombi . In addition, the interaction of cancer cells with immune cells (such as monocytes or macrophages) can induce a prothrombotic state .
The interaction with cancer cells, monocytes or macrophages release TNF-α, IL-1 and IL-6, which causes endothelial damage, converting the vascular lining into a thrombogenic surface .
The interaction between tumor cells and macrophages also causes platelet, factor XII, and factor X activation with subsequent induction of thrombosis .
Cancer and tissue factor
Cancer cells produce an abnormal amount of tissue factor (TF), a procoagulant protein critical to cancer-associated thrombosis (CAT) . TF promotes the extrinsic coagulation pathway by binding and stabilizing factor VII, activating downstream factors IX and X, and inducing thrombin and fibrin formation .
Malignant cells can release TF on the surface of extracellular vesicles, which is linked to the acceleration of the formation of thrombi. Pancreatic cancer cells produce a lot of macrovesicles, which explains the higher incidence of CAT . In addition, TF can be released by macrophages or monocytes and be released in extracellular vesicles .
Cancer cells and cytokine release
Cancer causes an inflammatory response that leads to cytokines release with different procoagulant capabilities. For example, TNF-α, IL-1, IL-1b and IL-6 induce von Willebrand factor and TF expression on vascular endothelial cells and monocytes. Additionally, these cytokines can inhibit the thrombomodulin and protein C anticoagulation. Thrombomodulin can bind to thrombin and cause its fast inactivation .
TNF-α has also been shown to increase extracellular vesicle release from cancer cells, with elevated TF activity seen on extracellular vesicles derived from lung, pancreatic and colon cancer .
Cancer cells and extracellular vesicles
Extracellular vesicles are particles released from cells and delimitated by a lipid bilayer. Cancer cells can shed extracellular vesicles, which contain surface protein and cargo, such as DNA, RNA, proteins and lipids rafts .
Extracellular vesicles have procoagulant activity because of their negatively charged plasma membrane, a catalytic surface for factors, such as factor VII, IX, X and prothrombin .
Extracellular vesicles also contain procoagulant activity depending on their method of formation and cargo content. In addition, they can contain TF and inflammatory molecules .
Cancer cells and neutrophils
As said before, neutrophils can release TF and extracellular vesicles. But neutrophils can participate in thrombi formation also through a physiological response to an infection called neutrophil extracellular traps (NETs). NETs are web structures composed of DNA and coated with histones and proteases. NETs can release von Willebrand factor through activation of endothelial cells leading to platelet adhesion and aggregation, which is essential for the formation of thrombi. In addition, NETs can provide a direct platform and scaffold for platelet aggregation .
During thrombus formation, neutrophils are the first leukocytes to arrive at the site of injury. In addition, several inflammatory factors (such as IL-8 and TNF-α) can induce the production of NETs, which serve as a scaffold for platelets, red blood cells and other procoagulants .
Additionally, the histones present in NETs activate platelets through TLR2 and TLR4, leading to thrombin generation. In addition, histones induce endothelial cells to release von Willebrand factor, which bind to glycoprotein Ib (GPIb) on platelets, influencing clot initiation .
Cancer and platelets
Platelets play a crucial role in thrombus formation, and their interaction with cancer cells can enhance their activation and aggregation .
Platelets are activated and adhere to endothelial damaged sites after binding to von Willebrand factor through GPIb. GPIb is part of the GPIb–V–IX complex. The von Willebrand factor recruits platelets via binding to the platelet receptor GPIbα, which is critical for platelet adhesion . As a result, cancer cells secrete platelet-activating factors leading to platelet aggregation.
Platelet-tumor interaction has an important role in metastasis too. Platelets can cover tumor cells, protecting them from the immune cells and allowing their adhesion to endothelium. This facilitates tumor cells’ extravasation at distant tissue sites. The same mechanisms can play a role in CAT .
Risk factors for CAT
Several risk factors are associated with CAT and can be classified in patient-, cancer-, and treatment-related risk factors.
Age above 65 years, female sex, black ethnicity, and comorbidities can increase the risk of venous thromboembolism (VTE) in cancer patients . In addition, prior VTE, infections, obesity, anemia, pulmonary or renal diseases can play a role .
Patients with cancer might go through a prolonged period of immobilization because of their therapies or oncologic pain. Reduced mobility impairs venous drainage and increases VTE risk .
Circulatory stasis might be triggered by cancer itself too. For example, tumors can cause bulky vascular compression, which reduces local blood flow .
Cancer treatment can require multiple surgical procedures or long-term catheters and chemotherapy that increase the risk of blood clots . Erythropoietin and anti-angiogenic therapies were shown to be associated with increased risk of VTE as well .
Why aggressive antitumor therapy, such as the use of platinum compounds or high doses of fluorouracil mitomycin and growth factors, can increase the risk of thrombosis is not fully understood. But all these agents can induce vascular damage, which can trigger blood clot formation .
Central venous catheters have a thrombogenic surface that can activate platelets and serine proteases like factor XII and X. In addition, Gram-negative and Gram-positive organisms can infect these catheters releasing endotoxin and bacterial mucopolysaccharides, respectively. These molecules activate factor XII and induce a platelet-release reaction, increasing the risk of thrombosis. In addition, endotoxin induces the release of TF, TNF-α, and IL-1, which trigger thrombogenesis .
Certain types of cancer carry a higher risk of VTE compared to others. For example, hematological malignancies, lung, pancreas, stomach, bowel, and brain cancers are associated with an increased risk, while prostate and breast cancers are associated with a low risk of thrombosis. However, prostate and breast cancer possess a high prevalence, making VTE common in these types of cancers .
Higher tumor grade and metastatic disease carry a higher risk of VTE, and genetic and epigenetic alterations in cancer tissues influence the development of CAT. Genetic alterations in the tumor itself may contribute to a hypercoagulable state and modulate CAT development. For example, mutations in PTEN and KRAS predispose to CAT, while mutations in IDH1/2 are inversely correlated with CAT in patients with glioma [8,9]. In addition, the epigenetics mechanism can further increase the risk of CAT.
Several risk assessments models have been developed to help the prediction of VTE risk in cancer patients. We discussed these with Prof. Pabinger and Prof. Gerotziafas.
Keep reading “Risk prediction for cancer‐associated thrombosis: A talk with Prof. Pabinger” and “Risk assessment models for venous thromboembolism in ambulatory patients with cancer: A talk with Prof. Gerotziafas.”
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