Introduction

Thrombosis is the abnormal formation of blood clots within blood vessels and is a major contributor to cardiovascular disease.¹ However, it also represents a major cause of mortality in cancer patients.² To understand the link between thrombosis and cancer, it is essential to first explore what thrombosis is and how it can pose serious health risks.

What is thrombosis? 

Typically, blood clots form to seal a break in our blood vessels caused by an external injury, such as cuts.³ This response helps prevent major blood loss and blocks the entry of pathogens that could cause infections.³ While this clotting system is effective for protection, it can also be triggered by internal damage within blood vessels (arteries or veins), leading to clot formation within the vessel itself.³ This can happen in cases where high blood pressure causes stress and injury to the inner part of the artery walls, triggering a series of reactions known as the clotting cascade.³ When a clot forms inside a blood vessel, it can reduce or completely obstruct blood flow, potentially leading to serious complications such as a stroke or heart attack.³

This raises an important question: how exactly does cancer play a part in the blood clotting process? In this article, we will explore:

• The disease mechanism of cancer-associated thrombosis
• Risk factors of thrombosis in cancer patients 
• The signs and symptoms of thrombosis in cancer 

Disease mechanism of cancer-associated thrombosis (CAT) 

Blood clotting mechanism

When an injury occurs, activation of the clotting cascade is essential to orchestrate the repair of the damaged blood vessel.⁴ This process can be divided into two main stages, which are outlined below. 

Stage 1: Weak platelet plug forms as a temporary solution

1. The process begins with the walls of the blood vessels contracting, causing them to become narrow.⁴ The narrowing of the vessel is required to minimise blood loss, as it reduces blood flow to the injury site⁵
2. Circulating platelets (small cell fragments in the blood) adhere to the exposed collagen of the damaged vessel wall⁴  
3. Upon binding, the platelets become activated, undergoing a shape change from smooth, disc-like structures to irregular forms with surface projections⁴  
4. These projections increase their surface area and enhance their ability to stick to one another, forming a clump of platelets, i.e. the weak platelet plug⁴

Stage 2: The platelet plug is then reinforced into a clot by a network of proteins known as fibrin

5. A series of complex biochemical reactions is then triggered, which leads to the activation of protein factor Xa⁴ 
6. Factor Xa contributes to the formation of the enzyme complex prothrombinase⁴ 
7. Prothrombinase then helps convert prothrombin into its active form, thrombin⁴ 
8. Thrombin catalyses the conversion of fibrinogen (a soluble plasma protein) into fibrin, an insoluble protein.⁴ This provides structural support that holds the clot in place by reinforcing the weak platelet plug⁴ 

How does cancer induce the blood clotting mechanism? 

All cellular processes are tightly controlled by intricate regulatory networks, which involve both activatory signals and inhibitory checkpoints. These systems ensure that processes are initiated only when required and suppressed when unnecessary, thereby conserving energy and maintaining internal stability. 

In cancer, however, genetic mutations disrupt this system, resulting in abnormal cellular behaviour.⁶ While such mutations are primarily associated with uncontrolled cell division, they can also activate other disease mechanisms, such as thrombosis.^2,6 In addition to the tumour itself, other factors in cancer patients contribute to the risk of thrombosis, as outlined below.² 

Tissue factor 

Malignant cells can promote coagulation either by initiating the clotting cascade, leading to the activation of factor Xa, or by releasing substances that directly activate factor Xa.² The subsequent formation of fibrin offers a survival advantage to cancer cells by creating a protective barrier against immune responses and certain therapies, while also providing a scaffold that promotes the spread of cancer cells.^7,8 Whilst the mutation causes tumour progression, it also significantly increases the likelihood of thrombotic events.

Anticancer therapy

Chemotherapy agents such as cisplatin, methotrexate, doxorubicin, and 5-fluorouracil have been associated with an increased risk of both venous and arterial thrombosis.² For instance, cisplatin has been shown to induce endothelial damage (damage to the inner lining of blood vessels), which directly activates the clotting cascade and plays a significant role in promoting thrombosis.⁸ 

Compression

The tumour itself can press against nearby blood vessels, reducing blood flow, which can cause damage to the endothelial cells.² This can then initiate the clotting cascade and increase the risk of thrombosis.² 

Prolonged immobility

Critically ill patients who are confined to prolonged bed rest have a higher risk of thrombosis in their legs.² This is because physical inactivity reduces blood flow to the legs, which can damage the endothelial cells of the blood vessels, thereby activating the blood clotting response.⁴

Risk factors for thrombosis in cancer patients

There are several different risk factors in cancer patients that need to be considered, as they can result in thrombosis. These can be divided into patient characteristics, tumour factors and treatment-related factors.¹⁰ 

Patient characteristics

Age, sex, and ethnicity

Individuals who are older in age, male, or of African descent have been associated with a higher incidence of CAT.^2,11,12 

Medical history

A prior history of thrombosis, cardiovascular disease, or inherited clotting disorders can significantly increase the risk of thrombotic events in cancer patients.²

Immobility

As described above, prolonged bed rest can directly contribute to thrombosis by reducing blood flow to the legs.²

Tumour factors

Site of cancer

Venous thromboembolism (VTE) typically includes conditions such as deep vein thrombosis (DVT) and pulmonary embolism (PE), which involve clot formation in the legs or lungs, whereas arterial thrombosis includes conditions like stroke and heart attack, resulting from clots obstructing arteries that supply the brain or heart.¹³

Cancers associated with a higher risk of DVT and PE include those affecting the pancreas, uterus, lungs, stomach, and kidneys.¹⁴ On the other hand, cancers associated with a higher risk of stroke include those affecting the lung, pancreas, colon and rectum.¹⁵ 

Stage of cancer

Cancers can be diagnosed at different stages, which helps indicate the extent of spread throughout the body. Early-stage cancers are generally localised, confined to the tissue it has originated from which typically makes them easier to treat.¹⁶ In contrast, late-stage cancers are more aggressive, as they are more likely to have metastasised to other tissues and organs, causing more damage to the body.¹⁶ 

The stage of cancer is a significant risk factor for CAT, as studies have shown a strong correlation between metastatic cancer and the increased incidence of thrombotic events.¹⁴ 

Time after diagnosis 

The risk of CAT is highest within the first three to six months following a cancer diagnosis, as this period is often marked by the initiation of aggressive treatments that can promote blood clot formation.¹⁴ 

Treatment-related factors 

Surgery 

Cancer patients undergoing surgery face a significantly elevated risk of thrombotic complications, with the incidence of DVT being approximately twice as high, and PE nearly three times as likely, compared to non-cancer patients undergoing similar surgical procedures.¹⁴

Cancer treatments

Chemotherapy, a highly aggressive form of cancer treatment, is strongly associated with thrombosis, as it increases the likelihood by six to seven times. This heightened risk is primarily driven by chemotherapy-induced endothelial damage and the subsequent activation of blood clotting pathways, as described above.¹⁴ 

Central venous catheters

Many cancer patients will need to insert a long, thin tube into a large vein, known as a central venous catheter (CVC), to deliver chemotherapy or collect blood samples.¹⁷ However, once inserted, CVCs can trigger blood clotting and inflammatory responses.¹⁸ Thrombotic obstruction often arises when fibrin accumulates around the catheter tip, significantly increasing the risk of localised thrombosis.¹⁸

Signs and symptoms of thrombosis in cancer  

The signs and symptoms of CAT vary depending on the location - specifically, whether it forms in a vein or an artery. Below are the characteristic symptoms associated with venous and arterial thrombosis in cancer patients.

Venous Thromboembolism (VTE)

Deep vein thrombosis (DVT)

• Swelling, usually in the leg¹⁹
• Pain or tenderness¹⁹  
• Warmth and redness over the affected area¹⁹  

A blood clot forming in the leg can travel to the lungs, where it can block an artery causing symptoms of a PE (see below).

Pulmonary embolism (PE)

• Sudden shortness of breath²⁰ 
• Chest pain that worsens with deep breaths²⁰ 
• Rapid heartbeat²⁰
• Coughing, possibly with blood²⁰ 
• Dizziness or light-headedness²⁰

Arterial thrombosis

Stroke

• Sudden weakness typically on one side of the body²¹
• Facial drooping²¹
• Difficulty speaking or understanding speech²¹

Heart attack

• Chest pain or discomfort²²
• Shortness of breath²² 
• Fatigue or weakness²²

Where to find support? 

Cancer is an emotionally challenging experience for both patients and their loved ones. If you need support, please do not hesitate to reach out to your healthcare team or connect with cancer support services, charities, or mental health professionals who can provide guidance.

Summary  

Cancer is strongly associated with an increased risk of thrombosis, making it a significant contributor to mortality in cancer patients. Under normal conditions, blood clots form through a tightly regulated cascade of biochemical reactions, typically initiated by blood vessel damage to prevent blood loss. However, cancer cells can aberrantly activate this coagulation cascade even in the absence of vascular injury. Besides the cancer itself, other risk factors such as chemotherapy and hospitalisation contribute to an increased risk of venous and arterial thrombosis. The clinical manifestations of CAT commonly include DVT, PE, stroke, and heart attack.