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VWF in Malignancy

In the Rutgers CLSC 5124 Advanced Hemostasis graduate course, a participant responded to  the question, “What do both Dr. Favaloro and Dr. Henry indicate about the role of platelets in metastatic carcinoma?.” The question referred to our Coag Conversations with Dr. Emmanuel Favaloro, The Many Faces of VWF. and with Dr. Brandon Henry, What Have We Learned about Inflammation and Thrombosis? The response:

VWF levels are markedly increased in cancer patients. Emerging data suggest that VWF may modulate angiogenesis, cell proliferation, and apoptosis, all of which represent different dysregulation pathways in cancer development and progression. Elevated plasma VWF:Ag levels have been reported in multiple cancer patient cohorts compared to normal healthy controls. This increase in WF:Ag levels is not limited to hematological malignancies, but has also been reported across a variety of solid tumors. A variety of endogenous agonists stimulate endothelial activation and VWF secretion, including thrombin, interleukins ( IL-6 and IL-8), histamine, and TNFα under inflammatory conditions. Tumor cells have also been shown to secrete soluble factors that induce Weibel-Palade body exocytosis. Therefore, tumor-mediated VWF secretion from endothelial cells is likely to contribute to the elevated plasma VWF:Ag reported in these patient cohorts.

While under normal conditions VWF production is limited to endothelial cells and megakaryocytes, some cancer cells of non-endothelial origin acquire de novo VWF gene expression. Examples include osteosarcoma cells SAOS2, colorectal cancer cells SW480, hepatocellular carcinoma cells HEPG2, and BEL7402, glioma cells M049, and gastric cancer cells BGC823, all of which have been shown to express VWF at both a protein and gene level. Expression of VWF within tumor cells induced the formation of endothelial Weibel-Palade body-like organelles called pseudo-Weibel-Palade bodies. No other markers of endothelial cells are expressed in these tumor cells, including CD31 and VEGFR2, which indicates that the acquisition of VWF expression is unique rather than a consequence of a phenotypic shift of the tumor cells towards an endothelial cell phenotype. There is an advantage for tumor cells to express VWF. Glioma and osteosarcoma cells have been shown to enhance tumor cell adhesion to endothelial cells as well as extravasation of the tumor cells across the endothelial barrier in vitro. Tumor-derived VWF also promotes the formation of tumor cell-platelet hetero-aggregates in vitro for osteosarcoma and gastric cancer cells. These hetero-aggregates, or platelet cloaking, have been proposed as an important mechanism to protect tumor cells from shear forces with the circulation and the assault of natural killer cells, and therefore, aid in metastasis.

Analysis of tumor tissues and plasma samples from melanoma patients revealed not only an increase in UL-VWF deposits along the tumor vasculature but also a reduction in ADAMTS13 activity. Bauer et al observed a marked decrease in local ADAMTS13 antigen and activity within tumor microvessels compared to healthy skin microvessels in vivo. Collectively, these results suggest the tumor cells increase UL-VWF secretion while simultaneously downregulating ADAMTS13 activity resulting in a prolonged half-life of UL-VWF multimers along the endothelial surface and a prothrombotic state.

Patmore S, et al. “Von Willebrand factor and cancer; metastasis and coagulopathies.” J Thromb Haemostas 2020;18:2444–56,

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