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Understanding the Mechanism Behind Blood Clots in Cancer Patients

New research from Weill Cornell Medicine, along with collaborators from Memorial Sloan Kettering Cancer Center and the University of California San Diego Health, has uncovered that the formation of blood clots in cancer patients is primarily driven by signals emanating from lung tissues rather than from other organs, challenging longstanding notions in the field. These clots are the second most common cause of mortality among patients suffering from advanced cancers or aggressive tumor forms.

Typically, blood clots are a natural response aimed at preventing excessive bleeding from injuries. However, in cancer patients, clots can develop without any external injury, leading to vessel obstruction and impaired blood flow to vital organs. The study, which appeared in Cell on February 11, reveals that tumors contribute to clot formation (thrombosis) by secreting specific chemokines. These proteins travel to the lungs, where they stimulate immune cells known as macrophages to release tiny vesicles that adhere to platelets, ultimately resulting in dangerous blood clots.

The implications of these findings are significant, as they may pave the way for new diagnostic tools aimed at assessing blood clotting risks and the development of targeted therapies to prevent clots at their source.

“This research fundamentally alters our understanding of thrombosis development in cancer,” said Dr. David Lyden, the principal investigator and a noted professor at Weill Cornell Medicine. “It reveals for the first time that the lungs play a critical role, a perspective that was largely overlooked until now.”

Co-authored by Dr. Diane Simeone, head of Moores Cancer Center at UC San Diego Health, and Dr. Jacqueline Bromberg, a breast cancer specialist at Memorial Sloan Kettering, the research sheds light on a pressing concern: “Many patients face a heightened risk of blood clots during their treatment. This study clarifies the underlying causes and opens avenues for innovative tests and therapies,” Dr. Bromberg emphasized.

Tumors in the Driver’s Seat

First author Dr. Serena Lucotti noted, “Post-mortem analyses indicate that nearly 60% of cancer patients succumb to blood clots rather than the cancer itself. Unfortunately, while there are medications available to prevent clots, they cannot be indiscriminately applied due to the risk of severe bleeding in some individuals. Simultaneously, identifying who is most at risk for clot formation has been a challenge.”

Through a series of experiments involving mice and human tissue samples, the researchers discovered that different types of tumors produce varying levels of the chemokine CXCL13. For instance, breast cancers and melanomas release relatively low amounts of this chemokine, but when they metastasize to the lungs, they can instigate clot formation through localized CXCL13 release. Conversely, pancreatic cancer is particularly noteworthy, as it secretes high levels of CXCL13 into systemic circulation, affecting distant macrophages in the lungs without requiring direct presence.

Blocking Clots — and Metastases

Further experiments demonstrated that upon interaction with CXCL13, lung macrophages release vesicles containing integrin β2, a molecule that facilitates platelet attachment and subsequently clot formation. Remarkably, when mice were administered an antibody designed to block this integrin from binding with platelets, they did not experience adverse bleeding effects. More significantly, these mice exhibited not only a reduction in clot formation but also a noteworthy decrease in metastatic spread compared to untreated counterparts. “This finding is crucial as there are limited effective treatments for patients facing metastasis, warranting further exploration,” stated Dr. Lucotti, who is in the process of developing a human antibody aimed at disrupting the integrin β2-platelet interaction in clinical settings.

The potential of integrin β2 also lies in its ability to serve as a biomarker for predicting blood clot risks. The research team analyzed blood samples from pancreatic cancer patients at Moores Cancer Center to successfully differentiate between low-risk and high-risk individuals based on integrin β2 levels present on extracellular vesicles in their blood, underscoring the promise of this approach.

This study reinforces the understanding that cancer impacts the body in numerous ways. “Cancer is inherently a systemic illness. We must consider not only prospective metastasis sites but also other organs that may be affected by systemic complications such as thrombosis, which can significantly influence patient health outcomes,” Dr. Lyden remarked.

This study received support from multiple organizations, including the United States Department of Defense and the National Cancer Institute, among others.

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