VWF fibers induce thrombosis during cancer

In this issue of Blood, Bauer et al¹  provide an explanation for the formation of luminal von Willebrand factor (VWF) fibers observed in cancer patients, which is initiated through tumor-derived vascular endothelial growth factor-A (VEGF-A). Platelet aggregation on VWF fibers correlated with a prothrombic state associated with decreased a disintegrin-like and metalloproteinase with thrombospondin type I repeats 13 (ADAMTS13) activity in cancer patients.

The association between cancer and thromboembolism was first described by Trousseau more than 100 years ago, when he made the astute observation that patients with unexplained thrombosis sometimes had an occult malignancy.²  The frequently observed prothrombic state in cancer patients encompasses a broad variety of complications, ranging from thrombotic microangiopathy to deep vein thrombosis. The pathophysiology of cancer-associated thrombosis is rather complex, but can be linked to 3 major features: stasis, vascular injury, and hypercoagulability, according to the criteria of so-called Virchow triad.³  Vascular alterations are frequently observed both in the primary tumor and at metastatic sites. Increased presence of VWF in the circulation correlates with endothelial damage and is used as an indicator for many pathological situations, including atherosclerosis, cardiovascular disease, and cancer.⁴  VWF forms polymer fibers attached to the luminal endothelial cells that contribute to hemostasis-mediating platelet adhesion. This process is normally controlled by the plasma metalloprotease ADAMTS13.⁴  However, VWF fibers also promote platelet aggregation, which may result in pathophysiological thrombi formation and vessel occlusion.⁵  In the current work, Bauer et al¹  show that VWF fiber formation and the associated platelet aggregation is detected both in primary tumors of melanoma patients and in a mouse melanoma model. Although a clear increase in VWF fiber formation was detected in melanoma patients, there was a small but significant decrease in ADAMTS13 in the tumors. However, enhanced VWF fiber formation in mouse melanoma tumors was associated with a clearly reduced ADAMTS13 activity. Consequently, intravenous infusion of recombinant ADAMTS13 significantly reduced luminal fiber formation in mouse tumors.

What causes endothelial damage during cancer progression that results in enhanced thromboembolism is still heavily debated. It is well known that a variety of procoagulant factors secreted by tumors such as tissue factor, thrombin, VEGF, mucins with selectin binding sites, or tumor necrosis factor has been shown to be abnormally raised during cancer and is linked to a prothrombic state in patients.^2,3,6  In addition, these factors have been shown to trigger thrombosis in a variety of animal cancer models. In particular, VEGF is the primary factor inducing angiogenesis and therefore both physiological and pathophysiological activation of the endothelium. Previously, thrombin release by melanoma cells was shown to induce endothelial activation associated with VWF deposition in the vascular lumen.⁷  Bauer et al now provide evidence that tumor-derived VEGF causes endothelial activation, resulting in enhanced VWF fiber deposits in the vasculature and thereby inducing platelet aggregation and thrombosis.

There is abundant literature on the use of heparin and low-molecular-weight derivatives (LMWH) in cancer patients. However, there is accumulating evidence that heparins have cancer inhibitory activity that goes beyond just anticoagulation.⁸  Although a rigorous evaluation of heparin or LMWH on inhibition of cancer progression is still missing, virtually all animal models confirmed beneficial effects of heparin or LMWH on cancer progression.^9,10  Because of the complex biological nature of heparins, they can affect several potential mechanisms involved in metastasis, including cell adhesion through selectins, enzymatic activity of heparanase, or the activity of growth factors and cytokines. The study by Bauer et al¹  now provides evidence that LMWH tinzaparin directly binds to VEGF and thereby reduces melanoma-induced endothelial activation associated with VWF fiber formation. These findings show yet another mechanism for how heparins may interfere with endothelial activation and angiogenesis. Long-term tinzaparin treatment of transgenic mice, which spontaneously develop skin melanomas, significantly prolonged survival in these mice. In particular, reduced VEGF amounts in tumors and reduced tumor cell proliferation were affected by tinzaparin treatment, which likely reflect a reduced angiogenesis and cancer progression.

Taken together, the work of Bauer et al¹  provides an important contribution to our understanding of cancer-induced prothrombic activity with regard to endothelial activation and VWF fiber formation in the lumen of cancer-associated vasculature. Although this work convincingly shows the relevance of VWF fibers formation and associated platelet aggregation in primary tumors of cancer patients, the fundamental question as whether VWF fiber formation occurs during metastatic initiation requires further investigation. Along these lines, the current findings show that endothelial activation is a critical requirement for successful metastasis. A better understanding of molecular events leading to VWF fiber deposition and subsequent microthrombus formation could allow the designing of new therapy approaches.