Anticoagulation inhibits tumor cell-mediated release of platelet angiogenic proteins and diminishes platelet angiogenic response.
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.
Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston MA;
Elisabeth M
EM
Battinelli
Beth A
BA
Markens
Rajesh A
RA
Kulenthirarajan
Kellie R
KR
Machlus
Robert
R
Flaumenhaft
Joseph E
JE
Italiano
D042501:Angiogenic Proteins / Q000378:metabolism; D000925:Anticoagulants / Q000378:metabolism / Q000627:therapeutic use*; D001777:Blood Coagulation / Q000187:drug effects; D001792:Blood Platelets / Q000166:cytology* / Q000378:metabolism; D000077425:Fondaparinux; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D061986:MCF-7 Cells; D008856:Microscopy, Fluorescence; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D010975:Platelet Aggregation Inhibitors / Q000378:metabolism; D011134:Polysaccharides / Q000494:pharmacology; D044463:Receptor, PAR-1 / Q000819:agonists / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D042501:Angiogenic Proteins; D000925:Anticoagulants; D010975:Platelet Aggregation Inhibitors; D011134:Polysaccharides; D044463:Receptor, PAR-1; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000077425:Fondaparinux