Why Does Pancreatic Cancer Cause Blood Clots?

Pancreatic cancer is one of the most aggressive malignancies, often leading to complications beyond tumor growth. One serious issue is an increased risk of blood clots, known as cancer-associated thrombosis, which can cause life-threatening conditions like deep vein thrombosis (DVT) and pulmonary embolism (PE).

Understanding why pancreatic cancer promotes clot formation requires examining how the disease alters normal blood coagulation processes.

Tumor-Derived Coagulation Factors

Pancreatic cancer cells actively manipulate the coagulation system by releasing prothrombotic factors that disrupt normal hemostatic balance. A key contributor is tissue factor (TF), a transmembrane glycoprotein that initiates the extrinsic coagulation cascade. Elevated TF expression in pancreatic tumor cells and their microenvironment leads to increased thrombin generation and fibrin deposition. A study in Blood found that pancreatic cancer patients with high TF expression had a significantly greater risk of venous thromboembolism (VTE), underscoring its role in clot formation.

Beyond TF, pancreatic tumors secrete microparticles—small vesicles from cancer cells carrying procoagulant molecules. These microparticles not only transport TF but also expose phosphatidylserine, a phospholipid that enhances coagulation complex assembly. Research in The Journal of Thrombosis and Haemostasis showed that cancer-derived microparticles accelerate thrombin generation, amplifying clot formation in patients. Their presence in circulation correlates with increased thrombotic events, making them a potential biomarker for assessing clotting risk.

Another contributor to hypercoagulability is the overproduction of mucins, high-molecular-weight glycoproteins secreted by pancreatic tumor cells. Mucins interact with P- and L-selectins on endothelial cells and platelets, promoting adhesion and clot formation. A study in Cancer Research highlighted that mucin-induced platelet aggregation plays a direct role in thrombosis, particularly in mucinous adenocarcinomas of the pancreas. This mechanism further exacerbates the prothrombotic state, creating a cycle where tumor-derived factors continuously fuel clot development.

Pro-Inflammatory Cytokines

Pancreatic cancer fosters a highly inflammatory environment that significantly contributes to blood clot formation. One of the primary drivers is the excessive release of pro-inflammatory cytokines, signaling molecules that mediate systemic inflammation. Among these, interleukin-6 (IL-6) plays a central role by upregulating fibrinogen synthesis in the liver and enhancing TF expression on endothelial cells and monocytes. A study in The Lancet Oncology found that pancreatic cancer patients with high circulating IL-6 concentrations had a significantly greater incidence of VTE.

Tumor necrosis factor-alpha (TNF-α) further promotes clot formation by disrupting the anticoagulant properties of the vascular endothelium. This cytokine downregulates thrombomodulin and endothelial protein C receptor, two critical components of the anticoagulant protein C pathway. Without sufficient protein C activation, thrombin generation proceeds unchecked, creating a hypercoagulable state. Additionally, TNF-α stimulates the release of von Willebrand factor (vWF) from endothelial cells, promoting platelet adhesion and aggregation. A study in Blood Advances found that pancreatic cancer patients with high TNF-α levels exhibited increased vWF activity, reinforcing the link between systemic inflammation and thrombosis.

Interleukin-1 beta (IL-1β) also contributes to clot formation by inducing the expression of plasminogen activator inhibitor-1 (PAI-1), which suppresses fibrinolysis, the process that breaks down blood clots. By inhibiting fibrinolysis, IL-1β prolongs clot stability, increasing the likelihood of persistent thrombi. Research in The Journal of Clinical Investigation found that pancreatic cancer patients with elevated IL-1β and PAI-1 levels had a higher risk of DVT, indicating that impaired clot resolution is a significant factor in cancer-associated thrombosis.

Endothelial Disruption

The integrity of the vascular endothelium is crucial in preventing excessive clot formation, but pancreatic cancer introduces multiple pathological changes that compromise this protective barrier. Tumor-secreted factors, mechanical stress from circulating cancer cells, and metabolic alterations weaken endothelial function, creating conditions that favor thrombosis.

One of the earliest disruptions occurs through direct endothelial cell damage, where pancreatic tumor-derived exosomes transfer oncogenic proteins and microRNAs that alter endothelial gene expression. This reduces nitric oxide production, a molecule essential for maintaining vascular homeostasis, increasing endothelial permeability and susceptibility to clot formation.

As endothelial integrity deteriorates, adhesion molecules such as E-selectin, P-selectin, and intercellular adhesion molecule-1 (ICAM-1) increase. These molecules facilitate platelet and leukocyte binding to the vessel wall, accelerating clot initiation. Elevated P-selectin levels, in particular, have been observed in pancreatic cancer patients with high thrombotic risk, as these molecules mediate platelet-endothelium interactions that promote clot growth.

Beyond biochemical changes, physical alterations in the vasculature contribute to endothelial dysfunction. Tumor-induced angiogenesis, driven by vascular endothelial growth factor (VEGF), leads to structurally abnormal, leaky blood vessels. These fragile vessels create areas of turbulent blood flow, increasing shear stress on endothelial cells and promoting localized thrombosis. Studies using intravital microscopy have demonstrated that disrupted microvasculature in pancreatic tumors is a common site for clot formation.

Platelet Activation

Platelets play a central role in blood clot formation, and pancreatic cancer profoundly alters their behavior, driving a hypercoagulable state. Tumor cells release factors that enhance platelet aggregation, creating an environment where clot formation occurs more readily. One significant change is the upregulation of platelet surface receptors such as glycoprotein IIb/IIIa, which strengthens fibrin cross-linking and stabilizes thrombi. This receptor becomes hyperactive in pancreatic cancer patients, increasing the likelihood of persistent clot formation. Elevated platelet counts, known as thrombocytosis, are frequently observed, further compounding the risk.

Beyond receptor activation, pancreatic tumors stimulate platelets to release procoagulant granules containing adenosine diphosphate (ADP) and thromboxane A2, both of which amplify platelet aggregation and reinforce clot stability. This feedback loop ensures that once platelet activation begins, clot growth accelerates. Additionally, circulating tumor cells can directly bind to platelets, cloaking themselves from immune detection while simultaneously triggering further platelet activation. This interaction enhances thrombus formation, as clinical studies have linked heightened platelet activity with increased rates of VTE.