Anticoagulation inhibits tumor cell–mediated release of platelet angiogenic proteins and diminishes platelet angiogenic response

• Published in: Blood 2014-01, Vol.123 (1), p.101-112
• Main Authors: Battinelli, Elisabeth M., Markens, Beth A., Kulenthirarajan, Rajesh A., Machlus, Kellie R., Flaumenhaft, Robert, Italiano, Joseph E.
• Format: Article
• Language: English
• Subjects: Angiogenic Proteins - metabolism; Anticoagulants - metabolism; Anticoagulants - therapeutic use; Blood Coagulation - drug effects; Blood Platelets - cytology; Blood Platelets - metabolism; Fondaparinux; Human Umbilical Vein Endothelial Cells; Humans; MCF-7 Cells; Microscopy, Fluorescence; Neovascularization, Pathologic - metabolism; Platelet Aggregation Inhibitors - metabolism; Platelets and Thrombopoiesis; Polysaccharides - pharmacology; Receptor, PAR-1 - agonists; Receptor, PAR-1 - antagonists & inhibitors; Receptor, PAR-1 - metabolism; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2013-02-485011

Platelets are a reservoir for angiogenic proteins that are secreted in a differentially regulated process. Because of the propensity for clotting, patients with malignancy are often anticoagulated with heparin products, which paradoxically offer a survival benefit by an unknown mechanism. We hypothesized that antithrombotic agents alter the release of angiogenesis regulatory proteins from platelets. Our data revealed that platelets exposed to heparins released significantly decreased vascular endothelial growth factor (VEGF) in response to adenosine 5′-diphosphate or tumor cells (MCF-7 cells) and exhibited a decreased angiogenic potential. The releasate from these platelets contained decreased proangiogenic proteins. The novel anticoagulant fondaparinux (Xa inhibitor) demonstrated a similar impact on the platelet angiogenic potential. Because these anticoagulants decrease thrombin generation, we hypothesized that they disrupt signaling through the platelet protease-activated receptor 1 (PAR1) receptor. Addition of PAR1 antagonists to platelets decreased VEGF release and angiogenic potential. Exposure to a PAR1 agonist in the presence of anticoagulants rescued the angiogenic potential. In vivo studies demonstrated that platelets from anticoagulated patients had decreased VEGF release and angiogenic potential. Our data suggest that the mechanism by which antithrombotic agents increase survival and decrease metastasis in cancer patients is through attenuation of platelet angiogenic potential. Key Points