CAT - Types, Pathogenesis, and Management

Introduction

The link between thrombosis (the formation of blood clots) and cancer was first discussed by Armand Trousseau in 1865. Based on different published studies and research, thrombosis is one of the most common complications of cancer, resulting in increased morbidity and mortality ratios worldwide. The complications of thrombosis related to cancer can vary from artery (arterial thromboembolism- circulating blood clots causing obstruction) to vein (venous thromboembolism) and DIC (disseminated intravascular coagulation). Although the facts about the relationship between thrombosis and cancer are quite clear to researchers, the pathology of the thromboembolism mechanism in cancer patients is yet notclearly understood.

This article focuses on the mechanism, etiology, risk, prevention, and management of cancer-associated thrombosis.

What Are the Types of Cancer-Associated Thrombosis?

Different types of cancer-associated thrombosis are:

A. Venous Thromboembolism (VTE): It mostly involves pulmonary embolism (the formation of the blood clot in one of the arteries of the lungs) and DVT (Deep vein thrombosis) - a blood clot formation in the deep vein (mostly the legs). It results in dysfunction of the endothelium (although it is intact) due to a decrease in the blood supply, reduced shear stress, and a lack of adequate oxygen supply to tissues (hypoxia). In individuals with cancer, it results in decreased blood supply to the heart from the legs via veins (venous stasis). The risk factors contributing to the development of VTE in cancer are:

1. Venous Stasis:

• Prolonged immobility after surgery.

• Compression of vessels by increased growth of tumor.

2. Hypercoagulability:

• Angiogenic injury (injury to blood vessels).

• Active chemotherapy.

• Hormonal therapy.

• Individuals with recent major surgery.

• Procoagulant effects (enhanced thrombi formation).

3. Endothelial Injury:

• Chemotherapeutic agents.

• Damaged endothelium.

• Late complications of radiation therapy.

• Endothelium invasion by tumor growth.

B. Arterial Thromboembolism: It is usually associated with damage to the endothelium. A plaque affected by atherosclerosis becomes susceptible to thrombosis when it exhibits a core abundant in lipids and is accompanied by a thin fibrous covering. The incidence of arterial thromboembolism is around 1 to 4 percent, as per studies.

C. Disseminated Intravascular Coagulopathy (DIC): It is a rare but very serious complication of a procoagulant state associated with a cancer-associated thrombus. It can result in TMA (thrombotic microangiopathy - thrombosis involving even minute blood vessels such as capillaries and arterioles). DIC causes destruction of three components of host defense against thrombus in cancer patients:

1. The flow of blood (resulting in stasis).

2. Protein balance, such as procoagulants and anticoagulants, within the blood, is disturbed, leading to the activation of procoagulants in the blood circulation.

3. Activation of the walls of blood vessels results in an unnecessary increase in procoagulants.

What Are the Risk Factors of Cancer-Associated Thrombosis?

The risk factors for cancer-associated thrombosis are:

• Associated comorbidities (such as previous heart surgery, lung, and kidney disease).

• Anemia.

• Obesity.

• Advanced age.

• Female predilection (more common in females than males).

What Is the Mechanism of Cancer-Associated Thrombosis?

In individuals with cancer, there are changes in the body, such as coagulopathy (increased formation of blood clots), inflammation or swelling, and lack of oxygen content in the tissues (hypoxia). Various substances are released by the cancer-dividing genes and cells, which causes the initiation of a series of thromboembolic events that lead to the formation of blood clots. Cancer patients undergo different mechanisms of blood clot formation, unlike regular blood clot mechanisms, which are called cancer-associated thrombosis (CAT).

Cancer cells start producing tissue factors that initiate clot formation. These factors also activate other factors like factor VII (blood coagulation factor), which results in the formation of a complex between factor VII and tissue factor (TF). TF also activates factor X (Stuart Prower factor), which results in the formation of factor Xa, which further promotes clotting. This whole process not only forms clots but also stimulates platelets, which are blood cells that aid in clotting, leading to the formation of many clots in the blood vessels.

How Is Cancer-Associated Thrombosis Managed?

A few management strategies for cancer-associated thrombosis are:

• According to the guidelines, venous thrombosis associated with cancer is managed by

1. Cardiopulmonary support.

2. Thrombolytic therapy (medications such as anticoagulants (heparin) used to destroy the existing blood clots and prevent the formation of new clots). Unfractionated heparin or low-molecular-weight heparin is the first line of therapy for three to six months based on current guidelines by NCCN (National Comprehensive Cancer Network). In individuals with active bleeding and low platelet count (below 50,000 per microliter), mechanical prophylaxis is recommended. Mechanical prophylaxis should be avoided in patients with DVT. In individuals with superficial venous thrombosis associated with a catheter, NCCN recommends anticoagulants after removal of a catheter. Six weeks of anticoagulant therapy is indicated in patients with non-catheter-related superficial venous thrombosis.

3. Surgery is considered based on the individual stage of cancer. It varies in different types and extent of cancer.

Cancer-related thromboembolism can occur due to anticancer agents used for the treatment of cancer, such as taxane-based anticancer drugs, angiogenesis inhibitors, and immunomodulatory drugs. It is essential to exercise caution. Prior to initiating anticancer therapy, patients should be evaluated for their risk of cancer-associated thrombosis (CAT) based on factors such as disease stage and the Khorana risk score. This assessment helps determine the most suitable treatment approach.

What Is the Prognosis of Cancer-Associated Thrombosis?

The mortality ratio is higher in patients with cancer-associated thrombosis, which is around 94 percent, as compared to non-cancer patients (29 percent). MI (myocardial infarction), ischemic stroke, and thromboembolic diseases are the most common causes of death in patients with cancer-associated thrombosis).

Conclusion

Cancer-associated thrombosis is a complex phenomenon that requires vigilant attention and management. Patients with cancer are at an increased risk of developing blood clots, which can lead to serious complications such as pulmonary embolism or stroke. The intricate interplay between cancer cells and the coagulation system of the body contributes to this heightened risk. Understanding the mechanisms underlying cancer-associated thrombosis is essential for devising effective preventive and therapeutic strategies. By implementing appropriate prophylactic measures and utilizing anticoagulant therapies judiciously, healthcare providers can significantly reduce the incidence of thrombotic events in cancer patients, thereby improving their quality of life and prognosis. Through interdisciplinary collaboration and ongoing research efforts, advancements in diagnosis, prevention, and management of cancer-associated thrombosis can be achieved, ultimately improving the quality of care and outcomes for individuals battling cancer.