The Intriguing Connections between von Willebrand Factor, ADAMTS13 and Cancer

Abstract

von Willebrand factor (VWF) is a complex and large protein that is cleaved by ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13), and together they serve important roles in normal hemostasis. Malignancy can result in both a deficiency or excess of VWF, leading to aberrant hemostasis with either increased bleeding or thrombotic complications, as respectively seen with acquired von Willebrand syndrome and cancer-associated venous thromboembolism. There is emerging evidence to suggest VWF also plays a role in inflammation, angiogenesis and tumor biology, and it is likely that VWF promotes tumor metastasis. High VWF levels have been documented in a number of malignancies and in some cases correlate with more advanced disease and poor prognosis. Tumor cells can induce endothelial cells to release VWF and certain tumor cells have the capacity for de novo expression of VWF, leading to a proinflammatory microenvironment that is likely conducive to tumor progression, metastasis and micro-thrombosis. VWF can facilitate tumor cell adhesion to endothelial cells and aids with the recruitment of platelets into the tumor microenvironment, where tumor/platelet aggregates are able to form and facilitate hematogenous spread of cancer. As ADAMTS13 moderates VWF level and activity, it too is potentially involved in the pathophysiology of these events. VWF and ADAMTS13 have been explored as tumor biomarkers for the detection and prognostication of certain malignancies; however, the results are underdeveloped and so currently not utilized for clinical use. Further studies addressing the basic science mechanisms and real word epidemiology are required to better appreciate the intriguing connections between VWF, ADAMTS13 and malignancy. A better understanding of the role VWF and ADAMTS13 play in the promotion and inhibition of cancer and its metastasis will help direct further translational studies to aid with the development of novel cancer prognostic tools and treatment modalities.

Toward 50 Years of Seminars in Thrombosis and Hemostasis

“…The VWF:CB remains a personal favorite of mine, and I still continue to publish on both the VWF:CB and VWD, with several related papers published in 2022. 2 3 4 5 6 Nevertheless, the VWF:CB does deserve another historical evaluation in STH, but this can await another issue in this series. I mention this in part because VWD was also a favorite of Eberhard's.…”

From the Discovery of ADAMTS13 to Current Understanding of Its Role in Health and Disease

“…116 This VWF/ADAMTS13 imbalance leads to platelet adhesion to tumor cells and fibrin deposition and it has been associated with venous thrombosis occurrences in patients with different types of cancer, 112,117 including hematological malignancies. 118,119 Both VWF and ADAMTS13 are involved in the pathophysiology of hematological and nonhematological tumors and disease progression. Therefore, approaches to control the increased VWF-ADAMTS13 axis in these conditions may require.…”

To Clot or Not to Clot: Is That the Question?

“…Another final example of increased thrombosis risk associated with the disease that I will provide is the state of cancer [ 10 , 11 ]. For example, in cancer patients, pulmonary embolism (PE) is the second leading cause of death after cancer itself, possibly because of difficulties in diagnosing the disease due to its nonclassical presentation [ 10 ].…”

“…Unfortunately, too little plasma VWF can instead lead to bleeding, with this condition arising in the common congenital bleeding disorder called von Willebrand disease (VWD) or in acquired von Willebrand syndrome (AVWS) [ 12 ]. Regarding the interconnectedness of all things, VWF and ADAMTS13 have intriguing connections with both cancer and cardiac disease that go beyond those of bleeding or thrombosis risk [ 11 ]. For example, VWF may assist certain cancers to spread or metastasize [ 11 ].…”

“…Regarding the interconnectedness of all things, VWF and ADAMTS13 have intriguing connections with both cancer and cardiac disease that go beyond those of bleeding or thrombosis risk [ 11 ]. For example, VWF may assist certain cancers to spread or metastasize [ 11 ]. In terms of cardiac disease, VWF may be implicated in both increased bleeding risk and increased thrombotic risk [ 13 ], depending on the type of cardiac disease and the plasma level and activity of VWF.…”